What Are The Uses Of Phenoxybenzamine Hydrochloride Biology Essay

What Are The Uses Of Phenoxybenzamine Hydrochloride Biology Essay Phenoxybenzamine Hydrochloride (RS)-benzyl(2-chloroethyl)1-methyl-2-phenoxyethylamine hydrochloride is a alpha-adrenoceptor blocker that covalently binds and irreversibly inhibits the activity of alpha-1 alpha -2 adrenoceptors.3,4 Phenoxybenzamine Hydrochloride is mainly used to treat episodes of high blood pressure and sweating related to phaeochromocytoma. Phaeochromocytoma is a rare catecholamine-secreting tumour of the adrenal medulla. Patients with phaeochromocytoma are usually hypertensive and suffer headache, palpitations, and excessive sweating.3 However it is rarely prescribed due to it unfavourable side effects. One of the side effects of Phenoxybenzamine is that block the ejaculation. Also some studies are under investigation to use Phenoxybenzamine as male contraceptive pills.11 , HCl Fig. 01 Molecular structure of (RS)-N-benzyl-N-(2-chloroethyl)-1- phenoxy-propan-2-amine Phenoxybenzamine hydrochloride is white, odourless, crystalline powder that is sparingly soluble in water; soluble in ethanol, chloroform, and propylene glycol; and insoluble in diethyl ether. Neutral and alkaline solutions are unstable; sensitive to oxidation and photo degradation.6,7,8 Molecular Weight9: 303.82638 [g/mol] Molecular Formula : C18H22ClNO MonoIsotopic Mass9: 303.138992 CAS-No. : 63-92-3 The stability studies for Phenoxybenzamine injection concentrate were carried out by Zeta Analytical Ltd. for their Clients. Also analytical method for related substance of Phenoxybenzamine Injection has been validated by them. During the stability studies, it has been found that some stability batches contain more than 0.1% of unknown impurities. Already there are three identified, process related impurities were reported in their clients analytical methods.10 Those three impurities A, B, and C are reported as shown below. 1. Impurity A: N-benzyl-N-(2-chloroethyl)-2-phenoxypropan-1-amine Fig. 02 Molecular structure of N-benzyl-N-(2-chloroethyl)-2- phenoxy-propan-1-amine 2. Impurity B: N-benzyl-N-(2, hydroxyethyl)-1-phenoxypropan-2-amine Fig. 03 Molecular structure of N-benzyl-N-(2-hydroxyethyl)-1-phenoxypropan-2-amine 3. Impurity C: N-(2-chloroethyl)-1-phenoxypropan-2-amine Fig. 04 Molecular structure a of N-(2-chloroethyl)-1-phenoxypropan-2-amine According to the International Conference on Harmonization1,2 (ICH) guidelines any component of a pharmaceutical product which is not the chemical entity of active substance or excipients, present at levels higher than 0.1% or 1 mg/day intake (whichever is lower) for a maximum daily dose of 2 g/day or less, need to be identified and qualified with appropriate toxicological studies. For a daily dose of greater than 2 g of drug substance, the identification threshold is 0.05%.1 ,2 Also British (BP), European (EP) and United states (USP) pharmacopeia texts refers the ICH criteria on impurity profiling for new drug substance and new drug products.5,6,7 Hyphenated techniques such as LC-MS and LC-NMR methods as an effective tool for characterization of impurities and degradation products in drug molecules. Therefore, Zeta Analytical proposed this project to perform LC-MS analysis on Phenoxybenzamine injection for structural elucidation of unknown impurity. This project involved method transferring (Tech transfer) from Zeta to Kingston University and developing a LC-MS compatible chromatographic method structural identifications of unknown impurity. Literature Study: There are no chromatographic methods have been reported in the literature describing the analysis of Phenoxybenzamine and its related substances using UV detection. The chromatographic Conditions mentioned in United States Pharmacopoeia (USP) monograph7 (refer Appendix) and Zetas method quiet similar apart from the detection wavelength, which is 268nm for USP and 220 nm for Zeta. Both methods are not compatible for LC/MS analysis. Because phosphate buffer is a one component that mobile phase consist in both methods. There are no reports available on the investigation using LC/MS/MS and isolation of related substances in Phenoxybenzamine active pharmaceutical ingredient (API). However, in order to analyse the sample in LC/MS and to get better chromatographic resolution the method has been modified for use in the present investigation. A synthesis route of Phenoxybenzamine has been mentioned in Vardanyan and Hruby,18 and slightly different route of synthesis for phenoxybenzaime related amines has been reported in Giardink et al.13 EXPERIMENTAL Material and Methods Chemicals used (all anal. Grade )were: Phenoxybenzamine Hydrochloride ( Sigma- Aldrich) , Impurity B (PBA) from med alchemy S.L Spain, HPLC grade Acetonitrile (Sigma- Aldrich), Potassium phosphate dibasic, Potassium phosphate monobasic, Ammonium formate, Ammonium Hydroxide, MilliQ grade water Samples Phenoxybenzamine injection concentrate ; Each 2 ml ampoule contains 100 mg Phenoxybenzamine Hydrochloride BP and excipients are absolute ethyl alcohol, hydrochloric acid AR and propylene glycol. Sample Preparation for HPLC and LC-MS Whole contents of ampoule was transferred to a 100mL volumetric flask and dissolved with 30 mL of acetonitrile. Then it was shacked for few minutes to mix well and added more acetonitrile to volume up the level of volumetric flask. HPLC analysis at Zeta Analytical Ltd. HPLC analysis was proceeded at these chromatographic condition : Column Phenomenex Gemeni-NX 5Â µm C18 110A 250-4.6 mm. Mobile phase used : pH 7.5 20mM Phosphate buffer (Dissolved 2.4g of K2HPO4 in 1L of water and adjusted to pH 7.5 with KH2PO4) : Acetonitrile = 30% : 70% (Isocratic mode ) .Column temperature 25C , flow rate 0.9 cm3min-1 , detection at 220nm . HPLC system used at Zeta analytical Ltd : Pump , Auto sampler ,UV detector and thermostat are Agilent 1100 series with Agilent Chemstation for LC data system. HPLC analysis at School of chemistry and pharmacy, Kingston University: HPLC analysis was proceeded at these chromatographic condition : Column Phenomenex Gemeni-NX 5Â µm C18 110A 250-4.6 mm. Mobile phase used : pH 7.5 20mM Phosphate buffer (Dissolved 2.4g of K2HPO4 in 1L of water and adjusted to pH 7.5 with KH2PO4) : Acetonitrile = 30% : 70% (Isocratic mode ) .Column temperature 25C , flow rate 0.9 cm3min-1 , detection at 220nm . HPLC system used at Kingston University: Pump , Auto sampler ,UV-VIS detector and thermostat are Perkin Elmer series 200 with Totalchrom v6.2 software. LC- MS analysis at School of chemistry and pharmacy, Kingston University: LC-MS analysis was proceeded at these chromatographic condition : Column Phenomenex Gemeni-NX 5Â µm C18 110A 250-4.6 mm. Mobile phase used : pH 8.3 20mM Ammonium formate buffer (Dissolved 1.3g of NH4HCO2 in 1L of water and adjusted to pH 8.3 with NH4OH) : Aceotonitrile = 30% : 70% (Isocratic mode) .Column temperature 25C , flow rate 0.9 cm3min-1 , detection at 220nm . LC system : Pump , Auto sampler ,UV-VIS detector and thermostat are Perkin Elmer series 200 with Totalchrom v6.2 data system. Mass detetectors used : Two different mass detectors were employed : Waters Micromass LCT ESI-TOF-MS system with Mass Lynx 4.1 software Thermo TSQ Quantum Access system ( MSMS ) with Thermo Excalibur software RESULTS AND DICUSSION HPLC Analysis at Zeta Analytical Ltd. Initially the sample was analyzed in Agilent HPLC in Zeta Analytical Ltd. Based on the Zetas Analytical Method validation report for the related substance of Phenoxybenzamine HCl injection, the three identified impurities and one unidentified impurity were confirmed. Below the fig.05 (Appendix A-1) shows the peaks of Phenoxybenzamine and its impurities and the table 01 shows the retention time of those peaks. Fig. 05 HPLC chromatograms of Phenoxybenzamine HCl injections Table 01: Peaks and its retention time of Phenoxybenzamine (zeta) Peaks Retention Time / min Impurity C 5.2 Impurity B 7.3 Unidentified Impurity 8.6 Impurity A 18.2 Phenoxybenzamine 19.6 HPLC Analysis at Kingston University: (Method Transfer) The above results obtained at zeta were replicated again with Perkin-Elmer HPLC system in Kingston University. Same chromatographic condition was employed with same Phenomenex Gemeni-NX 5Â µm C18 110A 250-4.6 mm column . The fig.06 below show chromatogram of Phenoxybenzamine HCl injection analysis repeated at Kingston University(Appendix A-2). The peaks were interested and its retention times are shown in the table 02 below. Fig.06 HPLC chromatogram of Phenoxybenzamine HCl Injection (Kingston) Table 02. Peaks and its retention time of Phenoxybenzamine (Kingston) Peaks Retention Time / min Impurity C 5.0 Impurity B 7.0 Unidentified Impurity 8.4 Impurity A 17.9 Phenoxybenzamine 19.5 LC-MS Analysis of Phenoxybenzamine Injection Concentrate: Phosphate buffers are not compatible for LC-MS due to their non volatile nature. Since it was necessary to replace the phosphate buffer to a volatile buffer. Mean while the chromatographic development should not be changed. The ammonium formate buffers are widely used in LC-MS analytical methods and has buffering pH range (8.2-10.2) close to the previous phosphate buffers used which is pH 7.5 . 20mM ammonium phosphate buffer was prepared adjusted the pH to 8.3. The HPLC analysis previously performed was repeated with mobile phase of Ammonium formate buffer : Acetonitrile =30: 70 instead of mobile phase of phosphate buffer : Acetonitrile = 30:70 . The isolation of peaks and the resolution obtained in previous analysis was replicated. Fig. 07 Show the HPLC chromatogram of replicated results with Ammonium formate buffer and the table 03 show retention time and its corresponding peaks. Fig.07 HPLC chromatogram of PBA Injection Sample ( Modified Mobile phase for LC-MS analysis) Table 03: Peaks and its retention time of Phenoxybenzamine (Ammonium formate as buffer)The samples were run on HPLC several times and constant chromatographic development was observed. Hence the sample fractions of unknown impurity was collected several time during HPLC run for LC-MS (accurate mass measurement) and LC-MS/MS (selective ion monitoring) analysis. Peaks Retention Time / min Impurity C 5.3 Impurity B 7.3 Unidentified Impurity 8.7 Impurity A 18.5 Phenoxybenzamine 19.8 Accurate mass measurement with Time of Flight (ToF) mass detector Feasibility of TOF mass detectors has made it to be used widely for measurement of accurate mass. Several unknown impurity sample fractions were analyzed for the accurate mass measurement on Waters micromass LCT ESI TOF-MS and obtained the average of the accurate mass value of unknown impurity. Ionization technique is Electron spray Ionization and mass analyzer is Time of Flight analyzer in this instrument. Results were taken on positive mode ( M + H + ). Hence mass of one proton must be deducted from the spectral mass value to obtain the exact mass value of unknown compound. H1 mass is considered to be 1.007 Da in the calculation below. Table 03: m/z value of Peaks observed its corresponding calculated monoisotopic mass M + H + / Da Mass of Unknown Compound / Da 344.215 343.208 344.216 343.209 344.216 343.209 344.219 343.212 344.211 343.204 344.209 343.202 344.215 343.208 344.214 343.207 344.215 343.208 344.213 343.206 344.215 343.208 344.22 343.213 344.213 343.206 344.221 343.214 344.223 343.216 The average molecular weight and standard deviation of results are found to be 343.2086667 and 0.003754363 respectively. Above results were subjected to statistical evaluation using Microsoft excel spread sheet. At 99% confidence level the molecular weight of the unknown impurity is found to be 343.2086667 0.002497. Determination of Elemental Composition of unknown impurity. Using Mass Lynx 4.1 MS data management software possible elemental composition was obtained for the molecular weight of 343.209 with 200.0 mDa tolerance . It was able to exclude a large amount elemental composition to narrow findings. That is elimination of Chlorine in the composition . Because the mass spectrum of unknown impurity does not show the isotopic pattern for chlorine. i.e. When one Chlorine atom is present in a molecule, that will show a n/n+2 ratio of 100/32.4 (35Cl/37Cl ratio of 100/32.4). 15,16 Hence only C,H,N and O elements were limited on search. Still hundreds of composition are left to be examined to find correct elemental composition . The second exclusion that is Nitrogen rule14 which was used to eliminate many of those composition. Since the unknown impurity molecular weight is odd number, we can eliminate all the composition with the even number of nitrogen in list. The following table shows considerable elemental composition left after above two exclusions . Table 04. Possible elemental composition and its Monoisotopic mass Elemental Composition Calculated Monoisotopic mass C12H25N9O3 343.2080 C16H29N3O5 343.2107 C23H25N3 343.2048 C21H29NO3 343.2147 C12H29N3O8 343.1955 C15H29N5O4 343.2220 C24H25NO 343.1936 The monoisotopic mass of main active compound is 303.14 and it contains 18 carbon on that molecule. Unknown impurity has the monoisotopic mass value 40 amu higher than the active compound. Therfore if it is been assumed that unknown impurity has more than 18 carbon on its molecule, only two elemental composition would be remained. i.e. C23H25N3 (343.2048) and C24H25NO (343.1936). LC -MS/MS (Tandem mass )Analysis of Phenoxybenzamine HCl Injection Concentrate Thermo TSQ Quantum Access LC-MS/MS was employed for the selective ion monitoring. The unknown impurity fractions , Phenoxybenzamine HCl standard (sigma ) and Impurity B standard were analysed. Analysis of Phenoxybenzamine HCl standard Parameter used: Parent mass: 304.4 Scan time: 0.5000 Collision energy: 16 Collision gas pressure: 1.1 Barr Spray Voltage: 4000 Scan Mode: Product Ion Scan Fig. 08 Product ion scan mass spectrum of Phenoxybenzamine Standard Peaks at m/z 63, 84, 91,107,120, 135 and 212 were observed. The base peak is observed at m/z 91 benzyl fragment . It is stabilized by the resonance form of benzene.17 The following figure illustrates the break downs and its corresponding mass units observed in the product ion scan spectrum. Fig. 09 Illustration of break downs of Phenoxybenzamine Apart from the peaks illustrated on above figure, the peaks at m/z 120 arise due to mass unit CH2NCH2CH2Cl + H+ . This is the middle portion after the mass unit at m/z 91 and 93 break apart from the whole Phenoxybenzamine molecule. i.e M + H+ the molecular ion is m/z 304, but 304 (91+93) = 120 . Analysis of Impurity B standard Parameter used: Parent mass: 286 Scan time: 0.5000 Collision energy: 16 Collision gas pressure: 1.1 Barr Spray Voltage: 4000 Scan Mode: Product Ion Scan Fig. 09 Product ion scan mass spectrum of Impurity B Standard Product Scan spectrum shows peaks at m/z 84, 91,102,107,135,178,194 and 285. The base peak is m/z 91and the molecular ion is m/z 286. The following figure illustrates the break downs and its corresponding mass units observed in the product ion scan spectrum. Fig. 09 Illustration of break downs of Impurity B As seen in the Phenoxybenzamine product ion scan spectrum the removal of mass units m/z 91 and 93 also is observed in this Impurity B spectrum. i.e . there is a peak arise at m/z 102 , this is due removal mass units m/z 91 and 93 from the molecular ion m/z 286. [286-(91+93)=102] Analysis of Unknown Impurity Parameter used: Parent mass: 286 Scan time: 0.5000 Collision energy: 16 Collision gas pressure: 1.1 Barr Spray Voltage: 4000 Scan Mode: Product Ion Scan Fig. 10 Product ion scan mass spectrum of Unknown Impurity Product ion Scan spectrum shows peaks at m/z 84,91,107,119,135,152,160,178,251,267 and 344 . Here the molecular ion peak and base peak are same at m/z 344. This mass spectrum shows quiet similar fragmentation pattern with Phenoxybenzamine and the impurity B were analysed before. Peaks at m/z 84, 91, 93, 107, and 135 are found in all three , Phenoxybenzamine , Impurity B and unknown impurity product ion scan spectrum. Also as studied previously in the spectrum of PBA and impurity B, the deduction of the mass units m/z 91 and 93 from the molecular ion (m/z 344) results a obvious sharp peak at m/z 160. From the facts studied above in product ion scan mass spectrum and accurate mass measurement for elemental composition using TOF -MS , It can be hypothesized a structure of the unknown impurity . The proposed structure for unknown impurity is shown below in figure. Fig. 11 The Molecular Structure proposed for unknown impurity, N-benzyl-N-[(E)-2-phenylethenyl] -1- phenoxy-propan-2-amine The proposed structure can be rationalized with the product ion mass spectrum of unknown impurity. Following fig.12 shows the break downs of the unknown impurity that correspond to the peaks observed on mass spectrum. Fig. 12 Illustration of break downs of Unknown Impurity Most of the impurities found in pharmaceutical compounds usually process-related compounds; they are most probably structurally similar to the synthesized target drugs. It is prominent to study the synthesis route of active pharmaceutical ingredient (API), when the unknown impurity of drugs substance is been identified. Unfortunately the original synthesis route followed by the API manufacturer of Phenoxybenzamine is not known. The prediction for synthesis route of Phenoxybenzamine with possibilities for arising of other 3 Identified process related impurities (A, B, and C) is shown in the following scheme below based on Giardink(1995).13 + (a) (ii) (iii) (iv) (b) (v) (c) (d) (vii) (vi) (a)Oxidation ;(b) 1-phenylmethanamine, HC1/EtOH,molecular sieves 4A, NaBH3CN; (c) Br(CH2)2OH, K2CO3, EtOH; (d) SOCI 2, HCI (g), Benzene (i)phenol; (2)2-methyl oxirane ;(3)1-phenoxypropan-2-ol;(4) 1-phenoxypropan-2-one; (5) N-benzyl-1-phenoxypropan-2-amine; (6) 2-[benzyl(1-phenoxypropan-2-yl)amino]ethanol;(7) N-benzyl-N-(2-chloroethyl)-1-phenoxypropan-2-amine (Phenoxybenzamine) Scheme 1. Predicted synthesis route for Phenoxybenzamine Formation of Impurity A The reaction between phenol (i) and 2-methyl oxirane (ii) is SN2 nucleophilic substitution. Nucleophiles are more reactive to most substituted carbon of epoxides under acidic condition and least substituted carbon is favoured under basic condition.19 In this case carbon position 2 (fig.13) is favoured under basic condition and its form 1-phenoxypropan-2-ol ,which is the precursor molecule for PBA . Fig. 13 Structure of 2-methyl oxirane To very few extent the nucleophiles react at carbon position 3 will form 2-phenoxypropan-1-ol, which will lead to the formation of Impurity A along synthesis process of PBA. Fig.14 Structure of 2-phenoxypropan-1-ol Formation of Impurity B and Impurity C Impurity B, 2-[benzyl(1-phenoxypropan-2-yl)amino]ethanol is intermediate product during synthesis. Refer structure (vi) of scheme 01 . Impurity C, N-(2-chloroethyl)-1-phenoxypropan-2-amine formed due to chlorination of intermediate product 1-phenoxypropan-2-ol (refer structure (iii) of scheme 01). The unoxidised 1-phenoxypropan-2-ol left over is chlorinated by SOCI 2, HCI during last step of the synthesis. Refer (d) of the scheme. CONCLUSIONS Preliminary structural assignments for unknown impurity of Phenoxybenzamine Injection were made on the basis of mass spectral data. Initially the works started with transferring HPLC method from Zeta Lab to Kingston university and developing a LC-MS chromatographic method. Ammonium formate volatile buffer was replaced for phosphate buffer in HPLC method . Same chromatographic development was able to replicated with ammonium formate buffer. Accurate mass measurement was carried out on ESI-TOF LC-MS . Also this studies led to determine possible empirical formula . Then LC-MS/MS analysis was performed. The Product ion Scan mass spectral data are very vital information in final structural elucidation of unknown impurity. The structure deduced from MS/MS confirms the empirical formula C24H25NO that derived with LC-TOF-MS spectral data. Eventually the impurity identified in this this preliminary structural assignments , which eluted at retention time of 8.7 minute was predicted as N-benzyl-N-[(E)-2-phenylethenyl] -1- phenoxy-propan-2-amine . The proposed molecular structure for unknown impurity is shown in fig.11 . The formation of impurities A, B and C those had already identified by manufacture were described based on the predicted synthesis route for Phenoxybenzamine . The formation unknown impurity was not able to explained at this stage of this project since the reaction would have occurred found to be more complicated. This project work was wrapped up at this stage due to time limitation. Further to these preliminary structural assignments various spectroscopic studies such as LC-NMR and IR need to be carried out to complete the characterization of the unknown compound. Ultimately the proposed st ructure can be confirmed by synthesizing N-benzyl-N-[(E)-2-phenylethenyl] -1- phenoxy-propan-2-amine in future.

Perils of Indifference Rhetorical Analysis Essay

At the end, and the start of a new millennium, or world has witnessed both atrocities and amazing displays of human compassion. In The Perils of Indifference Elie Wiesel successfully portrays his thoughts by applying anaphora’s, and the distribution of both ethos and pathos. Throughout his speech Wiesel repeats the word indifference quite often. An anaphora is the repetition of the same word or group of words in the beginning of successive clauses. â€Å"To be indifferent to that suffering is what makes the human inhuman. Indifference, after all, is more dangerous than anger and hatred.† Expresses the true emotional depth of the Holocaust by creating a mental picture of one having gone through pain and torture and have no emotion. By speaking with the appropriate pauses and tone, Wiesel’s audience felt what he was trying to convey. The display of pathos in his speech grasps the reader with the vast emotions and personal descriptions of his torment and others demise. â€Å"You fight it. You denounce it. You disarm it.†, is the rebel like feelings the prisoners continuously expressed. Finally ethos deals with credibility. Wiesel not only lived during the Holocaust, he survived it. He fought alongside many other Jews for their survival. He gives detail on and about his friends and family stationed at the camp with him. Wiesel goes in depth with the horrid memories he and many others endured. The Holocaust was like Hell on earth. During this era millions of Jews died for their beliefs. Wiesel has relived his experience multiple times in his book Night and his speech The Perils of Indifference. He uses anaphora’s and both ethos and pathos to successfully convey his thoughts and meanings of the Holocaust.

Biography Of Rachel Carson

A zoologist, biologist, environmentalist, writer, ecologist and a champion of nature conservation- Rachel Carson was all this and much more. From writing radio scripts during Depression to being the author of the best selling â€Å"Silent Spring† her journey was long, illustrious and motivational. The way she battled all odds, struggled with financial troubles and then later suffered all the indignities thrown at her after the publication of â€Å"Silent Spring† teaches us a lot about life and makes us look up to her with respect and admiration.Her early life was instrumental in making her the person she was. Her interest in nature was kindled during her childhood. Rachel Carson was born on May 27, 1907 of a father who was an ambitious real estate developer and a mother who was a teacher. Her father’s plans for their estate in Springdale, Pennsylvania did not quite materialize and thus from the very childhood, Rachel was no alien to financial difficulties. Her mo ther instilled in Rachel her own love for nature and books.Hence the training of a future environmentalist and a best selling author began early in life. Rachel started writing at a very early age and her publication was for a children’s magazine at the age of ten. Thus the die was cast and she was to follow this course till the very end of her life. After passing out from Parnassus High School, she enrolled in the Pennsylvanian college for Women (now Chatham College). She majored in English but later changed her subject to zoology.In 1932, Carson received her master’s degree. Her financial condition took a turn for the worse during the Depression and especially after the death of her father in 1935. Desperately trying to make ends meet for her family, she accepted the job of a radio writer for a programme on fishery and marine life produced by the United States Bureau of Fisheries. There seemed no end in sight to her miseries on the personal front. Her sister died in 1936, leaving behind two daughters.Carson took the girls in as part of family and they shifted to Silver Spring, Maryland to counter problems like her commutation to her job, the girls’ education and her mother’s old age. Following her excellent performance in the civil services examination, Carson went out to become the first ever female biologist to work at the Bureau. This was the beginning of a career that would see her influence the whole world with her writings.Her essay â€Å"Undersea†, published by Atlantic Monthly in September 1936, was the much needed and richly deserved breakthrough for her dual career. Bringing in rave reviews from scientists as well as literary circles, it lent weight to Carson’s belief that she could synchronize both her interests- of writing as well as nature- successfully. Impressed by her writing flair and lyrical style, famous author Hendrik William Van Loon (â€Å"The Story of Mankind†) persuaded his publisher to contact Rachel Carson who agreed the â€Å"Under the Sea Wind†.Presenting a naturalist’s picture of oceanic life, this book was a beautiful and sensitive description of the struggle for life of aquatic species. Her writing prowess succeeded in making an extremely engrossing reading out of scientific facts. The book was well received in both scientific and literary circuits. However it was not a commercial success as the release clashed with Pearl Harbor and consequently sales dipped.During World War II, she worked in the capacity of the Assistant to the Chief of the Office of Information in the Fish and Wildlife Service. Food was in short supply and her four pamphlets involving information on fish as food served multiple purposes of information source for print as well as radio media. Her series of twelve booklets, four of them authored by her, called â€Å"Conservation in Action† came out in the post war years.They propagated her ideal views of co- existence o f nature and humans and sought to inspire in people a respect for nature and an attitude for conservation. In 1948, she was appointed the editor- in- chief of the information Division- a noteworthy achievement in a male dominated profession. Meanwhile her research on the oceanic world continued in all the leisure time that she could afford. This research was what made the â€Å"The Sea Around Us† the bestseller that it was.â€Å"The Sea Around Us† was a bestseller beyond everyone’s imaginations. The pre- publication release of the first chapter by Yale Review was just the beginning of the fanfare. Carson won the George Washington Science Writing Award. When it was finally released by Oxford University Press in 1951, it was already a bestseller and topped charts for the following 81 weeks. In th euphoria created by â€Å"The Sea Around Us† , her publisher decided to re release â€Å"Under the Sea Wind†.This book also got the success it deserved, tho ugh a little belated. The phenomenal success of both the books helped Carson get her finances in order and she was able to quit her job at Fish and Wildlife Service to devote all her time to writing. â€Å"The Edge of the Sea† was published in 1955 and instantly became a huge success and remained so for the twenty- three weeks to come. It was a straight- from- the- heart account of the aquatic life on the sea shores.Again her writing capability and the deep seated feelings for oceanic species made it much more than a mere collection of scientific data and a dull set of guidelines. Around the same time, her article â€Å"Help your Child to Wonder† written for the women’s Home Companion, was another mover and shaker. In this article she gave directions to the parents to make their children aware of the wonders of nature and make them conscious of their natural environment.The personal touch that made the article strike a chord among the readers came from her own a ffection for her nieces and her grandnephew who she later adopted legally. An unmarried woman, with no children of her own, wrote the piece with all the nuances of a mother inspiring her children to look around with curiosity. In 1962, came the book that made the world sit up and notice. â€Å"Silent Spring† attracted many opinions; not all of them were flattering.Based on her research on the ill effects of pesticides on animal and human world, it brought a deluge of savage comments from those whose interests clashed with the ideas expressed in the book. Agricultural and trade journals, pesticide producers and owners of chemical factories- all attacked Carson and generated a lot of negative publicity. But nevertheless, â€Å"Silent Spring† appealed to the public and became a best seller. It generated a wave of environmental concerns. Even President John F.Kennedy was moved by the book and appointed a special panel to examine the various points the book raised. All the research, investigation and hard work that Carson had put in the book bore results and even the Presidential Committee confirmed Rachel’s concerns about the pesticides. The book raised genuine concerns about the concentration of DDT in the food chain and these timely concerns led to early action and averted what could have been a catastrophe after a few years.But what Carson had to suffer for making her views public was unbelievable. Her health failed her and yet she endured the barrage of ill meaning comments thrown at her after publication of â€Å"Silent Spring†. Breast cancer finally took its toll on her life and Rachel Carson died o April 14, 1964. Many laurels were bestowed on her during her lifetime and she deserved each one of them. She was presented with the Schweitzer Medal of the Animal Welfare Institute.She was also given the National Wildlife Federation’s â€Å"Conservationist of the Year†. But perhaps the greatest award was the response her readers gave her. Their admiration, adulation and their applause made her into an icon, a status she richly deserved. Her ideas of environmental concerns became really famous and common after her death. She was never against technology and development; it was only indiscriminate and reckless progress that irked her.She campaigned for controlled and calculated use of pesticides through her book â€Å"Silent Spring† Rachel Carson was responsible for environmental concern becoming the household term that it is now. Her revolutionary ideas set the trail for others to follow. Now the whole world has woken up to the harmful effects of pesticides to food chains. At that time, however she had been saddled with negative comments and personal humiliation. Her personal life was also littered with losses throughout.A spinster till death, she had to suffer a lot of speculation over her long and intimate friendship with Dorothy Freeman. A lot can be learnt from her life which was a roller coaster ride with many twists and turns. A rich and true tribute to her persona will be our waking up to the damage being done to our fragile eco- system and our efforts to rectify that. WORKS CITED â€Å"Breaking Nature’s Silence: Pennsylvania’s Rachel Carson† Lisa Budwig â€Å"Rachel Carson Dies of Cancer: ‘Silent Spring’ author was 56† Obituary, The New York Times. .

Napoleon Bonaparte’s Failed Invasion of Russia in 1812

Napoleon Bonaparte’s failed invasion of Russia in 1812 was the cause of his eventual downfall. To what extent do you agree with this statement? To a large extent, Napoleon Bonaparte’s failed invasion of Russia was the cause of his eventual downfall. In 1812 Napoleon marched with his Grand Army into Russia in an attempt to seize the country. The crushing defeat which followed devastated the army, leaving it incapacitated and vulnerable. This venture into Russia crippled Napoleon’s quest for European domination, and destroyed his fiercely defended reputation as an indestructible leader. While Napoleon was at war various coup d’à ©tat (overthrow) attempts were made back in France, showing that he had chosen an inopportune time to leave the†¦show more content†¦Napoleon made many mistakes in his invasion into Russia. He was a brilliant leader, but in the later years of his life his tactical genius faltered, perhaps due to illness. His invasion was planned with little preparation or focus, and without proper purpose. Napoleon may have been affected by illness, or even arrogance because of his previo us victories. He believed that he was infallible, and so he did not assess the situation correctly. His oversights cost him a victory and eventually his title as Emperor of France. The Russian campaign was the greatest catastrophe in his entire career and signalled to those opposing him that he was no longer indestructible. Prior to the defeat, many had believed Napoleon to be an undefeated military genius and because of this few wished to oppose him. The crippling Russian failure exposed a weakness which the enemies of France were quick to exploit. Napoleon himself realised this and hurried home to France in an attempt to stop news of the defeat from spreading, though this was in vain. Britain, Russia, Sweden and Prussia prepared to go to war with Napoleon. In the year following his defeat, Napoleon raised an army of around 400 000 to go to war against the allied powers. However, this army was inexperienced and outnumbered. The defeat of the Grand Army had rid France of its best so ldiers, and many in the new army had never fought before. Napoleon’s empire was collapsing on every front.Show MoreRelatedThe Mistakes of the Brilliant General, Napoleon Bonaparte Essays1026 Words   |  5 PagesThe assumption held by many that Napoleon Bonaparte was a brilliant general and an exceptional leader is debatable when the Frenchman’s many mistakes are revealed. Bonaparte was born to a wealthy family with previous political connections (Wilde 1). He entered a military academy at only nine years old and entered the French Army Artillery Regiment seven years later (Wilde 1). 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