Drug Research And Development Biology Essay

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Drug research development, production in pharmaceutical industry is dependent on elemental analysis, starting with the testing of individual ingredients and continuing through production to final quality control, as impurities can affect drug efficacy and metabolism. Heavy metals present in pharmaceutical products can be toxic even at trace levels exhibiting a significant health threat to consumers. In addition, these elements can also endanger the overall quality of the pharmaceutical product even without causing toxic effects because inorganic impurities such as copper, nickel, and cobalt reduces the shelf life by increasing the rate of free-radical formation and also enhancing the oxidative decomposition within the product. As a result, the accurate measurement of trace metals in pharmaceutical products is of utmost importance to ensure that the products are less toxic and free of elemental impurities [3]. Pharmaceutical products require routine screening of metals for two main reasons: [2]

Metals are essential components of the pharmaceutical product, e.g.organometallic-based drugs for ulcer treatment, cancer treatment, etc.

•

Metals can be present in the finished pharmaceutical product as a result of the following:- contamination during the manufacturing process- their use during the manufacturing process as catalysts

Metals are essential components of the pharmaceutical product, e.g.organometallic-based drugs for ulcer treatment, cancer treatment, etc.

•

Metals can be present in the finished pharmaceutical product as a result of the following:- contamination during the manufacturing process- their use during the manufacturing process as catalysts

Metals are essential components of the pharmaceutical product, e.g.organometallic-based drugs for ulcer treatment, cancer treatment, etc.

•

Metals can be present in the finished pharmaceutical product as a result of the following:- contamination during the manufacturing process- their use during the manufacturing process as catalysts

Metals are essential components of the pharmaceutical product, e.g.organometallic-based drugs for ulcer treatment, cancer treatment, etc.

•

Metals can be present in the finished pharmaceutical product as a result of the following:- contamination during the manufacturing process- their use during the manufacturing process as catalysts

Metals are essential components of the pharmaceutical product, e.g.organometallic-based drugs for ulcer treatment, cancer treatment, etcMetals are the most essential components in pharmaceutical products. eg. Organometallic-based drugs for Ulcer treatment, Cancer treatment, etc.

The presence of metals in the finished Pharmaceutical products because of either the contamination during manufacturing process of the drug product or their use during the manufacturing process as catalyst. The presence of MT(figure 1)

Figure 1: Tree-diagram for different sources of Pharmaceutical Impurities [24]

The pharmacopeial forum of USP has proposed two chapters-

Chapter I : Elemental Impurities-Limits.

Chapter II: Elemental Impurities-Procedures to replace the general test

Chapter-Heavy Metals. [5, 6]

The first chapter is proposed to set limits on amount of elemental impurities in pharmaceuticals. In this chapter elemental impurities are classified as shown in (Table 1).

TYPE

ASSESSMENT

Class-I

Elements should be essentially not present, known for strongly suspected human toxicants

Environmental hazards

Class-II

Elements should be limited

Elements deliberately added to an article

Table1: Elemental Impurity Classes [4]

Class 1 impurities: Class 1 elemental impurities (Table 2), because of their toxicity levels or deleterious environmental effects, such elements should not be present in a pharmaceutical drug substance, excipient, or final product. However, their levels should be restricted as shown in Table 2, if their presence is unavoidable unless otherwise stated in the individual monograph. [4]

Class 2 impurities: Class 2 elemental impurities (Table 2) should be restricted in drug substances, excipients, and pharmaceutical products because of their cumulative toxic effects. Based on the limit tests, determination of elemental impurities are performed for pharmaceuticals, excipients & drug products, as recommended by various pharmacopoeias. [4]

According to United States Pharmacopeia32/The National Formulary27 (USP 32/NF 27),

Chapter 191:Identification Tests-General, Class 3 Impurities such as Fe, Zn are the metals with minimal safety concern ie. Oral exposure PDE (μg /day) 13000, Concentration (ppm) 1300, while Parenteral exposure PDE (μg /day) is 1300 and concentration (ppm): 130. [25, 12]

Note: *Permitted Daily Exposure (PDE)

Element

Component Limit

(μg/g)

Oral Daily

Dose PDE*

(μg/day)

Parentral Component

Limit (μg/g)

Parentral

Daily Dose

PDE* (μg/g)

Class 1 Elemental Impurities

Arsenic

1.5

15

0.15

1.5

Cadmium

0.5

5

0.05

0.5

Lead

1

10

0.1

1

Mercury

1.5

15

0.15

1.5

Class 2 Elemental Impurities

Chromium

25

250

2.5

25

Copper

250

2500

25

250

Manganese

250

2500

25

250

Molybdenum

25

250

2.5

25

Nickel

25

250

2.5

25

Palladium

10

100

1.0

10

Platinum

10

100

1.0

10

Vanadium

25

250

2.5

25

Osmium

Rhodium Ruthenium Iridium

10

(combination not to exceed)

100

(combination not to exceed)

1.0

(combination not to exceed)

10

(combination not to exceed)

*Permitted Daily Exposure (PDE)

Table 2: Class I and Class II Elemental impurities [4]

Most common techniques such as atomic spectroscopy, voltammetry and X-ray methods are used in analysis but they have many limitations to determine the accurate concentration of each element. The pharmacopeial forum of USP has suggested use of techniques such as inductively coupled plasma-mass spectrometry (ICP-MS) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) for element determination. [4]

Inductively Coupled Plasma Mass Spectroscopy (ICP-MS)

Inductively Coupled Plasma Mass Spectroscopy (ICP-MS) is a spectral technique used to determine trace multi-elemental and isotopic concentrations in solid, liquid or gaseous samples [1]. It combines a high-temperature ion-generating argon plasma source (which converts the atoms of the elements in the sample to ions; temperature of around 6000-10000 K) with a mass spectrometer (which separates and detects the ions). In this case, the ions generated during the process are detected rather than the light they emit. The ions generated within the plasma passes through the mass spectrometer where they are separated in the magnetic field according to their mass-to-charge ratio (m/z) ratio by a quadrupole or magnetic sector analyzer. However, this technique uses a mass spectral detection, rather than wavelength-based detection. The detection limit for ICP- MS is 1 to 10 ppt (parts-per-trillion level). Schematic of ICP-MS IS:

Figure 2: Schematic of ICP-MS [9]

Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP-AES)

Inductively coupled plasma atomic emission spectroscopy (ICP-AES) is a spectral technique which is used to determine the elemental composition of samples and to measure the elemental concentration within the sample [1]. Hence this method is also called Multielemental spectral technique. In this method, we use high-energy plasma (Temperature of the plasma generally ranges from 6000 to 10,000 K.) from an inert gas like argon to burn analytes, so as to excite the atoms at higher energy levels. The plasma source is generated when argon gas is passed through an alternating electric field that is created by an inductively couple coil. In this method of analysis the atoms are excited from ground state to higher energy levels and the atoms soon drops back to ground state emitting excess energy in the form of light having specific intensity. In this case, the intensity of light is directly proportional to the concentration of the elements that is present. As a Rule of Thumb, the transitions (Resonance Transitions) to the ground state tend to be more sensitive. The wavelength of the emitted light depends on the energy difference between the excited energy level and the ground state. So, wider the energy difference, shorter the wavelength and smaller the energy difference wider the wavelength. In this way the wavelength of light can be used to determine what elements are present by detection of the light at specific wavelengths. The detection limits for these elements are typically at the 1 to 10 ppb (parts-per-billion level). Schematic of ICP-AES is:

Figure 3: Schematic of ICP-AES [8]

Applications of atomic spectroscopy (ICP-AES & ICP-MS) in the pharmaceutical industry for the determination of trace elements in pharmaceutical products

In pharmaceutical industry monitoring and impurity profiling of pharmaceutical drug products is a major area of concern. As compared to inorganic impurities, much is known about organic impurities, while the inorganic impurities are gaining more importance recently in pharmacy sector. These inorganic impurities (metal contaminants) enter the bulk drug substances and intermediates through raw materials, catalysts, reagents, solvents, various equipment's used for the synthesis of drug products. Therefore it is essential to monitor these metal ion contents in drug products. [10]

Analysis of Elements in Drug products (API/Raw material/Intermediates) using ICP-AES and ICP-MS:

Manufacturers of Active Pharmaceutical Ingredients (API's), Raw materials and Intermediates used in the pharmaceutical industry can use any number of elements (mentioned in periodic table) in various synthetic processes because pharmaceutical products and the raw materials used to prepare them, may come into direct contact with a variety of materials during manufacturing process. Variety of metals and metalloids are used in manufacturing process and they are also used as the active pharmaceutical ingredient (API) in drug products. [12]

For example: [12,14]

Lithobid® (LITHOBID®, USP (lithium carbonate) is an extended-release formulation containing 300mg of lithium carbonate, used in treatment of schizophrenia) in which significant metallic component is Lithium (Li).

Many other metals and metalloids may not represent a significant component in drug products, but they may be used in synthesis of drugs as reagent or as catalyst. Also it is of utmost importance to define their toxicity levels. For example: Pb, Hg, As and Cd, which are addressed by both the EMEA Guideline on Residues of Metal Catalysts and proposed USP Chapter 232.Palladium (Pd) and platinum (Pt) are the commonly used catalysts in the pharmaceutical industry. Example: European Pharmacopoeia (EP) has proposed a limit of 20 μg/g of Pt in calcium folinate [15].

As a drug product moves through the development process into the clinical phases, analytical testing requirements plays an important role, and metal testing is performed not only on the API, but also on intermediates, raw materials and equipment. Elemental analysis using atomic spectroscopy covers not only the API, but also cleaning validations and fingerprinting of drugs. [12]

La´sztity et al. [17](2002), demonstrated the usefulness of ICP-MS analysis for rapid screening of inorganic impurities in Bulk drugs such as Enalapril maleate, Calcium folinate and Levodopa to determine concentrations of elements such as Palladium, Platinum, and Rhodium. Screening was carried out for Rh, Pd, Pt, Be, V, Mn, Co, Ni, Cu, Zn, Mo, Cd, Sn, Th and Pb metals, by selecting Rh103, Pd105 and Pd106, Pt195 isotopes. The detection limits were 15 ng/g for Palladium in Enalapril maleate, 2.8 ng/g for Platinum in Calcium folinate & 2.5 ng/g for Rhodium in Levodopa, respectively. The Rh content in l-dopa was comparable to that determined by GF-AAS (0.1 μg/g detection limit).

ICP-AES method to determine content uniformity and distribution

Characteristics of drug in its tablets dosage form and granule

Wang et al. [18] developed a method to monitor drugs (investigational drug (A) in its calcium salt form) uniformity and distribution in granules and tablets during early stages of formulation and process development and to analyze calcium (the counter ion of the drug substance) and for by Inductively Coupled Plasma Atomic Emission Spectrometer (ICP-AES). This method has been validated to demonstrate satisfactory precision, accuracy, specificity and sensitivity (10 ppm). This method has also been used to analyze sieve fraction granules and tablets of drug compound A. Generated data were highly comparable to those by validated HPLC methods (UV method cannot be applicable due to significant bias). In comparison with HPLC methods (13 min/sample analysis time), this method demonstrates a significantly improved efficiency with very short analysis time (1 min/sample), and can be used as an excellent alternative for UV and HPLC methods to support fast paced formulation screening.

ICP-AES method to determine trace elements in Tablets and cosmetics

Salvador et al. [20] (2000) proposed and assayed methodologies for accurate determination of titanium oxide, zinc oxide and iron oxide in commercial sunscreen products. Titanium is determined by inductive coupled plasma emission spectrometry (ICP-AES). Zn and Fe were also determined by flame atomic absorption spectrometry (FAAS). The limit of detection of the ICP-AES determination of Ti was estimated in the order of 0.035 mg/ml. •

Metals are essential components of the pharmaceutical product, e.g.organometallic-based drugs for ulcer treatment, cancer treatment, etc.

•

Metals can be present in the finished pharmaceutical product as a result of the following:- contamination during the manufacturing process- their use during the manufacturing process as catalysts

Pharmaceutical products need to be routinely screened for metals for two dis-tinct reasons, namely:

•

Metals are essential components of the pharmaceutical product, e.g.organometallic-based drugs for ulcer treatment, cancer treatment, etc.

•

Metals can be present in the finished pharmaceutical product as a result of the following:- contamination during the manufacturing process- their use during the manufacturing process as catalysts

Pharmaceutical products need to be routinely screened for metals for two dis-tinct reasons, namely:

•

Metals are essential components of the pharmaceutical product, e.g.organometallic-based drugs for ulcer treatment, cancer treatment, etc.

•

Metals can be present in the finished pharmaceutical product as a result of the following:- contamination during the manufacturing process- their use during the manufacturing process as catalysts

Pharmaceutical products need to be routinely screened for metals for two dis-tinct reasons, namely:

•

Metals are essential components of the pharmaceutical product, e.g.organometallic-based drugs for ulcer treatment, cancer treatment, etc.

•

Metals can be present in the finished pharmaceutical product as a result of the following:- contamination during the manufacturing process- their use during the manufacturing process as catalysts

Pharmaceutical products need to be routinely screened for metals for two dis-tinct reasons, namely:

•

Metals are essential components of the pharmaceutical product, e.g.organometallic-based drugs for ulcer treatment, cancer treatment, etc.

•

Metals can be present in the finished pharmaceutical product as a result of the following:- contamination during the manufacturing process- their use during the manufacturing process as catalysts

Metals are essential components of the pharmaceutical product, e.g.organometallic-based drugs for ulcer treatment, cancer treatment, etc.

•

Metals can be present in the finished pharmaceutical product as a result of the following:- contamination during the manufacturing process- their use during the manufacturing process as catalysts

The relative standard deviation of the TiO2 content was in the 0.6-5% range. The limit of detection was 0.03 mg/ml for Zn and 0.02 mg/ml for Fe.

Zachariadisâˆ-et al. [19] (2009) developed a method for multi element analysis of sunscreen creams and lotion by using (ICP-AES), for quantitative determination of Ti and several minor, trace elements such as (Al, Zn, Mg, Fe, Mn, Cu, Cr, Pb and B) in the final products. The detection limits were 0.2μg/g for Ti, 0.2μg/g for Zn and 0.5μg/g for Fe. Possible interference because of Ti on the sensitivity of each analyte was examined and the method was applied successfully to several commercial sun protection products. The results were compared with those obtained by atomic absorption spectrometry as reference method. The next step was to study if high concentration of titanium, which may be present in several commercial sunscreen products thereby, producing interference in the determination of other analytes by ICP-AES. Finally, the effect of a high Ti concentration on the sensitivity of the determination of the other analytes was investigated. Inorganic analytes of interest can be determined in presence of higher titanium concentration without significant interference.

Recently, Zachariadis et al. [16] (2011) proposed a multi-element analysis method based on inductively coupled plasma atomic emission spectrometry (ICP-AES) to determine trace elements in pharmaceutical tablets and cosmetics. Titanium was also included in the analytes since it is widely used in pharmaceuticals because Titanium dioxide and Iron oxide are widely used as film coating materials for tablets and cosmetics. Detection limits were in the low µg g−1range (0.1-0.9 μg/g except for Pb for which higher LOD was obtained) were obtained. The method was applied to the analysis of six different pharmaceutical products (anti-biotic, anti-inflammatory, anti-hypertensive) in the form of tablets with film coating such as Cefadroxil, Omeprazole, Norfloxacin, Ranitidine hydrochloride or Propranolol hydrochloride as active substances, various excipients like Magnesium stearate, Titanium dioxide, Microcrystalline cellulose, Red iron oxide, Gelatine and also three cosmetic products like hair and face masks. Finally, Mg, Mn and Cr were found in the cosmetic creams.

ICP-MS method for determining metal concentration in Large Volume Parenteral Drug Products [13]

In a recent study by Harigaya et al., Kuwahara et al. (2008) [13], discuss the potential metals contamination in large volume parenterals (LVP's). i.e. The method was developed to determine concentration of aluminum (Al) in large volume parenteral (LVP) drug products used in total parenteral nutrition (TPN) therapy. The determination of Al in LVP drug products was performed by using, Inductively coupled plasma mass spectrometer (ICP-MS) equipped with a dynamic reaction cell (DRC-ICP-MS). The detection limit of Al in a 1% (v/v) HNO3 aqueous solution was found to be 2ng/l. Also the Al contents in LVP drug products were obtained by this method in the range of 1.16-4.33m g/l and were less than 25m g/l [within the regulation value of Food and Drug Administration (FDA)]. Each part of the LVP drug product (composed of three chambers), was investigated so as to trace the origin of Al in LVP drug products. Additionally, the Al contents in injection bags were measured. It was observed that Al contents in injection bags were relatively high (in the range of 27.5-33.6m g/g). Finally, it was concluded that, the Al contents in the LVP drug products investigated originated in the amount of the Al in each raw material.

Using ICP-AES to determine heavy metal concentrations in pharmaceuticals.

Stoica et al. (2004) discussed new method to determine the concentration of cobalt in pharmaceutical products (e.g. B12 vitamin powder, B12 ampoules) by spectrometric techniques such as (FAAS, GFAAS and ICP-AES) and electrometric (AdSV). The pharmaceutical products analyzed contain together with B12 vitamin microelements such zinc, molybdenum, chromium, nickel, vanadium, tin, manganese, copper, selenium, iron and another vitamins (A, E, C, B1, B2, B6, D, K). R.S.D (%) for Vitamin B12 powder 0.35 & for Vitamin B12 ampoules 0.17 by ICP-AES. Limits of detection LOD and limit of quantification LOQ for cobalt were 0.10 μg/L and 0.50 μg/L. For determining cobalt in these samples it was necessary to utilize sensitive and selective analytical methods. A good correlation was obtained between the values by FAAS, ICP-AES. The low cobalt content in some pharmaceutical products makes FAAS less useful but ICP-AES has some advantages because it offers multi element determination and is relatively free from interferences.

Using ICP-MS to determine heavy metal concentrations in drug substances.

In a recent study by A S R Krishna Murty et al.[10] selected drugs such as DicyclomineHCl, Ethambutol, Pyrazinamide and Furazolidone, were analyzed for trace levels of heavy metal ion contents. All these compounds contain nitrogen, which can bind the heavy metal ions through the lone pair of electrons on nitrogen. It was observed that Fe values were higher in case of ethambutol due to its ability to chelate with the metal ions resulting due to contamination while Co, Ni and Hg were not detected. The highest amount of Cu (21.6 ppb) in furazolidone might be due to the use of copper cathode in the preparation of furazolidone (involves electrolytic reduction of 3-nitro-2-oxazolidone at copper cathode in 10% sulphuric acid), whereas Co, Ni, Cd and Hg were not detected. In case of pyrazinamide, a higher value for Cr (11.5 ppb) and Cu (8.4 ppb) is because pyrazoic acid which is used as raw material in pyrazinamide synthesis using copper chromite as catalyst. But the higher value of Ti was unexplained. The proposed method is useful for determining heavy metal ion contents at trace levels in a single run thus, helpful in finding the roots of manufacturing processes of these drugs. In the above studies, two methods of sample preparation, (1) direct dissolution in 5% (v/v) HNO3 (2) digestion with HNO3 and H2O2 were compared and NIST 1643b (Trace elements in Water Reference Sample from National Institute of Standards and Technology, USA) was analyzed and found good agreement with a precision of <5% RSD (Table 3).

Table-3: Concentration of various trace elements (ng/ml) in NIST 1643b (water reference sample) in comparison with certified values [10]

NIST - (National Institute of Standards and Technology, USA)

ICP MS survey method as an alternate method to Heavy metal limit test for Pharmaceutical products

Official Pharmacopoeias (The United States Pharmacopoeia (USP), British Pharmacopoeia (BP), European Pharmacopoeia (EP) and Japanese Pharmacopoeia (JP)) describes heavy metal test method which consists of precipitation of heavy metals as sulphides from an aqueous solution and the visual comparison of the colour of that preparation with that obtained from similarly prepared solution of standard lead solution (dark brown). Various elements respond to the test by yielding different colours (white, yellow, orange, black and dark brown). It is difficult to identify for the ion of particular interest responsible for the colour, based on only colour as parameter. The lack of specificity, sensitivity and time consuming procedures provide no information about the recoveries. Attempts have been made to improve the efficacy of this method (Heavy metal limit test) but they are not of much advantage. The main disadvantage of using Heavy metal limit test is their suitability for few elements and unequal sensitivity. Although the toxicity of trace metal ions such as Hg, As, Pb is known, but their limits are not defined clearly in pharmaceutical products. AAS, ICP-AES and ICP-MS are suitable techniques for this propose. Among these techniques, ICP-MS is the most suited for multi-elemental analysis because of its very low detection limits (ppb, ppt) for most of the elements of the periodic table. [10]. Lewen et al. [23] (2004) also demonstrated the applicability of a general ICP-MS method as an alternative to the compendial methods for the determination of heavy metals. In any event, with the publication of the EMEA Guideline and the USP's proposed chapter 232, it is clear that the traditional limit test for elemental analysis in pharmaceuticals industry is no longer sufficient to meet the standards and needs of either the industry or patients.

CONCLUSION

One of the main differences between ICP-MS and ICP-AES is the way in which the ions are generated and detected. Both the methods are capable of very fast, high throughput multi-elemental analysis (10 - 40 elements per minute per sample) but, ICP-MS has a detection limit of a few ppt to a few hundred ppm as compared to the ppb-ppm range (1 ppb - 100 ppm) of ICP-AES. ICP-MS works over eight orders of magnitude detection level whereas ICP-AES which has six orders of magnitude detection level. For these reasons, a multi-element survey type ICP-MS method has been developed which is superior and has broad detection capability of various elements with greater precision (Short term precision: 0.5 to 2% and Long term precision: 2 to 4 %) and accuracy. Also because of the limitations in the 'heavy metals test' prescribed by USP, EP, and BP, this method is widely used as an alternate method for Heavy metal Limit test, which is of greater importance in Pharmaceutical Industry for monitoring of various drug products/processes.

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