PRESENCE OF ORGANIC IMPURITIES INTO ACTIVE PHARMACEUTICAL INGREDIENTS: A REVIEWHTML Full Text
PRESENCE OF ORGANIC IMPURITIES INTO ACTIVE PHARMACEUTICAL INGREDIENTS: A REVIEW
Rajat Ghosh *, Katon Darin and Panchali Deb
Department of Pharmacy, Tripura University (A Central University), Suryamaninagar - 799022, West Tripura, India.
ABSTRACT: The presence of an excess amount of pharmaceutical impurities in active pharmaceutical ingredients and control of these are a major issue for all pharmaceutical companies. It is essential to know the presence of impurities in the drug substances and control them up to a certain level to avoid adverse effects. Impurities in organic drug molecules can be developed during organic synthesis, formulation or upon aging of active pharmaceutical ingredients, which may affect the quality, safety, and efficacy of drugs. Impurity profile is defined as the description of identified and unidentified impurities present in new drugs as per ICH guidelines. The identification of the impurities of different drugs is done by a variety of available Chromatographic and Spectroscopic techniques. The different analytical methods are utilized for characterization and identification of impurities such as Capillary Electrophoresis (CE), Gas Chromatography (GC), Supercritical Fluid Chromatography (SFC), Thin Layer Chromatography (TLC), High Performance Thin Layer Chromatography (HPTLC), High Performance Liquid Chromatography (HPLC), UV-Visible, IR, Mass, NMR and Raman spectroscopy. In this review article, a study has been done on various well known marketed drugs for their organic impurities, those were reported by various researchers, and a list of few drugs is prepared, those were obtained from British Pharmacopeia 2007.
Active Pharmaceutical Ingredient (API), Chromatography, Impurity profile, Organic impurity, Spectroscopy
INTRODUCTION: The quality, safety, and efficacy of drug products are directly dependent on their toxicological properties and the presence of impurities. Various regulatory authorities like ICH, USFDA, Canadian Drug, and Health Agency are emphasizing on the significance of purity detection and the identification of impurities in Active Pharmaceutical Ingredients.
Biological safety can be achieved by evaluating and obtaining data on the presence of impurities in drug substances. That’s why impurity profiling is required to get an appropriate result from drug substances 1. The term ‘impurity’ can be defined as something that is impure or makes something else impure.
In the field of pharmaceutical sciences, mostly impurities in drug substances mean the presence of organic materials, inorganic residues, and residual solvents, besides the drug substance. Impurity profile is the description of identified and unidentified impurities present in new drug substances as per ICH guidelines.
It includes identification, structure elucidation, and quantitative determination of impurities and degradation products in bulk drug materials and pharmaceutical formulations.
It helps in identifying and quantifying the impurities present in drug substances (APIs) or pharmaceutical formulations 1-4.
Impurities have been named differently or classified as follows:
- Common Impurities: By-products, Degradation products, Interaction products, Intermediates, Penultimate intermediates, Related products, Transformation products.
- Various Pharmacopeia listed Impurities: Pharmacopoeias of various countries also mention impurities in various sections; Impurities in Official Articles, Ordinary Impurities, Organic Volatile Impurities, etc.
- As per ICH Terminology: According to ICH guidelines, impurities in the drug substances produced by chemical synthesis can broadly be classified into the following three categories;
- Organic Impurities (Process and Drug-related)
- Inorganic Impurities
- Residual Solvents 1
Organic Impurities: Organic impurities can arise in APIs or drug product formulations during the manufacturing process or during the storage of drug substances. They may be known, unknown, volatile, or non-volatile compounds with sources including starting materials, intermediates, unintended by-products, and degradation products. They may also arise from racemization or contamination of one enantiomeric form with another. In all cases, they can result in undesired biological activity.
- Starting Materials or Intermediates: These are the most common impurities found in every API unless proper care is taken in every step involved throughout the multi-step synthesis. In Paracetamol bulk, there is a limit test for p-aminophenol, which could be a starting material for one manufacturer or be an intermediate for another.
- By-products: In synthetic organic chemistry, getting a single end product with 100% yield is very rare; there is always a chance of having by-products. In the case of Paracetamol bulk, diacetylated paracetamol may form as a by-product.
- Degradation Products: Impurities can also be formed by degradation of the end product during the manufacturing of bulk drugs, storage or formulation to different dosage forms or aging. The degradation of Penicillins and Cephalosporins is a well-known example of degradation products. The presence of a ß-lactam ring, as well as that of an a-amino group in the C6/C7 side chain, plays a critical role in their degradation 4, 5.
Inorganic Impurities: Inorganic impurities can arise from raw materials, synthetic additives, excipients, and production processes used when manufacturing drug products. Sources of inorganic impurities include manufacturing process reagents such as ligands, catalysts (e.g., platinum group elements), metals derived from other stages of production (e.g., process water and stainless steel reactor vessels), charcoal, and elements derived from other materials used in filtration.
Residual Solvents: Residual solvents are the volatile organic chemicals used during the manufacturing process or generated during drug production. Several organic solvents used in the synthesis of pharmaceutical products have toxic or environmentally hazardous properties, and their complete removal can be very difficult 6.
Sources of Impurities: From the preceding discussion, it is clear that impurities can be originated from several sources such as; Crystallization-related impurities, Stereochemistry-related impurities, Residual solvents, Synthetic intermediates and by-products, Formulation-related impurities, Impurities arising during storage, Method related impurity, Mutual interaction amongst ingredients, Functional group-related typical degradation 1.
Different Methods to Identify Impurities:
- Spectroscopic Method: The UV-Visible, IR, Mass, NMR, and Raman spectroscopic methods are routinely being used for characterizing impurities.
- Separation Method: Capillary Electrophoresis (CE), Gas Chromatography (GC), Supercritical Fluid Chromatography (SFC), Thin Layer Chromatography (TLC), High-Performance Thin Layer Chromatography (HPTLC), High-Performance Liquid Chro-matography (HPLC) are regularly being used for separation of impurities and degradation products 4.
Identification of Impurities by Researchers: Thomas et al reported an unknown impurity in the drug Deferasirox. HPLC detected it and identified by (LC–ESI–QT/MS/MS). The impurity was confirmed as 2-[3,5-bis(2-hydroxy-phenyl)-[1,2,4]-triazol-1-yl]-benzoic acid 7.
3- [1- (dimethylamino) ethyl] phenyl N-ethyl-N-methyl carbamate N-oxide, Ethyl-methyl-carbamic acid 4-(1-dimethylamino-ethyl)-phenyl ester, ethyl-methyl-carbamic acid 2-(1-dimethylamino-ethyl)-phenyl ester impurities were reported by Thomas et al. in the drug Rivastigmine tartrate by using HPLC and LC/MS/MS method 8.
Gazdag M et al., confirmed the presence of 17α-Hydroxy-17-oic acid and 17α,20-Dihydroxy-21-oic acid impurities in Mazipredone by using HPLC-(APCI)-MS and HPLC- diode-array UV method 9.
Makino Y et al., determined the presence of (1R,2S)-(1)-ephedrine and (1S,2S)-(1) pseudo-ephedrine impurities in bulk Methamphetamine with the help of HPLC using two different columns: a phenyl-β-cyclodextrin- type column and an ODS-type column 10.
Choe S et al., identified the presence of pharma-ceutical impurities such as Acetaminophen, Caffeine, Chlorpheniramine, Phenacetin, Ambroxol, etc. in the drug Methamphetamine crystals seized in Korea by using the GC-FID and GC-MS method 11.
The presence of benzaldehyde and benzyl alcohol in the drug Methamphetamine was identified by Kuwayama K et al., by using the HS-SPME & GC-MS 12.
Trefi S et al., investigated different impurity profiles in generic Ciprofloxacin formulations collected from different countries by using 19F, 1H and DOSY NMR techniques. The impurities were 7- chloro- 1- cyclopropyl- 6- fluoro- 4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (fluoro-quino-lonic acid), 1-cyclopropyl-4-oxo-7-(piperazin -1-yl)-1,4-dihydroquinoline-3-carboxylic acid (des-fluoro compound), 7- [(2- aminoethyl) amino]-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (ethylenediamine compound) and 7-chloro-1-cyclopropyl-4-oxo-6-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid 13.
The presence of impurities in the antiparkinsonian drugs such as Levodopa, Carbidopa, Entacapone was identified by Vemi´c A et al., by using reversed-phase LC method. The identified impurities were (2S)-2-amino-3-(4-hydroxyphenyl) propanoic acid and (2RS)-2-amino-3-(4-hydroxy-3-methoxyphenyl)propanoic acid for Levodopa, Methyldopa, 3-O-methylcarbidopa for Carbidopa and (2Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N, N-diethyl-2-propenamide, and 3,4-dihydroxy-5-nitrobenzaldehyde for Entacapone 14.
Sun C et al., reported a novel impurity in bulk drug Eprosartan by a simple and sensitive HPLC/MSn and NMR method. The identified impurity was 4, 4’-(5,5’-(1E,1’E)-3,3-(4,4’-methylenebis (thiophene-4, 2-diyl))bis(2-carboxyprop-1-ene-3, 1-diyl) bis(2-butyl- 1H -imidazole-5, 1-diyl)) bis (methylene) dibenzoic acid 15.
Zhang D et al., isolated and identified three impurities 5-((4-fluorobenzyl)amino)- 2-oxo- 1H-imidazo[4,5-b]pyridine-1, 3(2H)-dicarboxylate, diethyl(6-((4-fluorobenzyl)amino)pyridine-2,3-diyl) dicarbamate and 5-((4-fluorobenzyl)amino)-1H imidazo[4,5-b]pyridin-2(3H)-one in the drug Flupirtine maleate, a centrally acting, non-opioid, nonsteroidal anti-inflammatory analgesic by using MS, 1H,13C, 2D NMR and IR 16.
Kadivar MH et al., prepared impurity profile on Febuxostat drug substance by LC-MS/MS technique. The impurities were first identified with the help of LC-MS/MS and characterized by IR and NMR. The impurities 2-(3-carbamoyl-4-iso butoxy phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid, 2-[4-(butan-2-yloxy)-3-cyano phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid, 4-methyl-2-[4-(2-methylpropoxy)phenyl]-1,3-thiazole-5-carboxylic acid, 2-(2-methylpropoxy)-5-(4-methyl-1,3-thiazol-2-yl)benzonitrile were found 17.
Volk KJ et al., mentioned the presence of impurities such as Norbutorphanol, 9-hydroxy-butorphanol, 9-keto-butorphanol, Ring-contracted butorphanol, Δ1, 10a-butorphanol in the drug Butorphanol tartrate by using LC-MS & LC-Tandem MS 18.
A list of several impurities present in various drugs identified by different methods is shown in Table 1, and a list of some well-known marketed drugs and their impurities mentioned in British Pharmacopoeia 19 is discussed in Table 2.
The structures of the aforementioned impurities are shown in Fig. 1.
TABLE 1: LIST OF IMPURITIES IDENTIFIED BY DIFFERENT METHODS
et al., 7
|HPLC & (LC–ESIQT/MS/MS)||Deferasirox||i)2-[3,5-bis(2-hydroxy-phenyl)-[1,2,4]-triazol-1-yl]-benzoic acid||1a|
et al., 8
|HPLC & LC/MS/MS||Rivastigmine tartrate||ii)3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methyl carbamate N-oxide
iii)Ethyl-methyl-carbamic acid 4-(1-dimethylamino-ethyl)-phenyl ester
iv)ethyl-methyl-carbamic acid 2-(1-dimethylamino-ethyl)- phenyl ester
et al., 9
|HPLC-(APCI)-MS & HPLC-diode-array UV||Mazipredone||v) 17α-Hydroxy-17-oic acid
vi) 17α,20-Dihydroxy-21-oic acid
et al., 10
et al., 11
|GC-FID & GC-MS||Methamphetamine||ix) Acetaminophen
|Kuwayama K et al., 12||HS-SPME/GC–MS||Methamphetamine||xii) Benzaldehyde
xiii) Benzyl alcohol
et al., 13
|19F, 1H & DOSY NMR||Ciprofloxacin||xiv) 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (fluoroquinolonic acid)
xv) 1-cyclopropyl-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (desfluoro compound)
et al., 14
|xvi) ((2S)-2-amino-3-(4-hydroxyphenyl) propanoic acid
xvii) (2RS)-2-amino-3-(4-hydroxy-3-methoxyphenyl)propanoic acid
et al., 15
|HPLC/MSn & NMR||Eprosartan||xxii) 4,4’-(5,5’-(1E,1’E)-3,3-(4,4’-
methylenebis(thiophene-4,2-diyl)) bis (2-carboxyprop-1-ene 3,1-diyl)bis(2-butyl-1H-imidazole-5,1 diyl))bis(methylene)dibenzoic
et al., 16
|MS,1H,13C, 2D NMR & IR||Flupirtine maleate||xxiii) 5-((4-fluorobenzyl)amino)-2-oxo-1H-imidazo[4,5-b]pyridine-1,3(2H)-dicarboxylate
et al., 17
|LC-MS/MS||Febuxostat||xxvi) 2-(3-carbamoyl-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid
xxvii) 2-[4-(butan-2-yloxy)-3-cyanophenyl]-4-methyl-1,3-thiazole-5-carboxylic acid
xxviii) 4-methyl-2-[4-(2-methylpropoxy)phenyl]-1,3-thiazole-5-carboxylic acid
et al., 18
|LC-MS & LC-Tandem MS||Butorphanol tartrate||xxx) Norbutorphanol
xxxiv) Δ1, 10a-butorphanol
FIG. 1: STRUCTURE OF IMPURITIES
TABLE 2: IMPURITIES OF FEW WELL-KNOWN MARKETED DRUGS AS PER BRITISH PHARMACOPOEIA:
DRUG NO. 01
DRUG NO. 02
DRUG NO. 03
DRUG NO. 04
DRUG NO. 05
DRUG NO. 06
DRUG NO. 07
DRUG NO. 08
DRUG NO. 09
DRUG NO. 10
DRUG NO. 11
DRUG NO. 12
DRUG NO. 13
DRUG NO. 14
DRUG NO. 15
DRUG NO. 16
DRUG NO. 17
DRUG NO. 18
DRUG NO. 19
DRUG NO. 20
DRUG NO. 21
DRUG NO. 22
DRUG NO. 23
DRUG NO. 24
DRUG NO. 25
DRUG NO. 26
DRUG NO. 27
CONCLUSION: Impurity profiling of a pharmaceutical substance under investigation gives a maximum possible description of impurities present in it. The establishment of regulatory guidelines for impurity levels in drug substances and products provides the quality criteria for manufacturers. These impurities are developed in pharmaceutical products during the manufacturing process, chemical synthesis, formulation, storage, etc. Various analytical tools have been used for the detection, identification, and characterization of various impurities in active pharmaceutical ingredients. From the above discussion, it has been observed that there are lots of impurities present in several well-known marketed drugs whose successful identification and control of the individual or total content as per pharmacopeias are needed to render biological safety and efficacy.
The present study throws the attention to the future researchers to set the impurity profiling as a paramount step in the process of quality control and to develop more sophisticated analytical techniques to detect the level of potent impurities present in drugs more accurately. Even in this article, we have tried to give a brief list of impurities of well-known marketed drugs, mentioned into British pharmacopeia. In the future, we would like to make a more improvised list of impurities with their content limits along with APIs of all well-known marketed drugs, listed in other pharmacopeias also.
ACKNOWLEDGEMENT: We are highly thankful to the Department of Pharmacy, Tripura University, for the vital contribution in the preparation of this paper.
CONFLICT OF INTEREST: Nil
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How to cite this article:
Ghosh R, Darin K and Deb P: Presence of organic impurities into active pharmaceutical ingredients: a review. Int J Pharm Sci & Res 2014; 5(10): 4078-08. doi: 10.13040/IJPSR.0975-8232.5(10).4078-08.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
R. Ghosh *, K. Darin and P. Deb
Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, West Tripura, India.
20 March 2014
20 May 2014
01 July 2014
01 October 2014