The Extraction And Purification Of Paracetamol Essay

The root And Purification Of Paracetamol look forAnalysing the Quantity and Purity of Paracetamol Present in Different Formulations of the Commercial medicinal drugAimThe aim of this investigating was to determine the parting by majority of consummate(a) paracetamol in formulations of mark paracetamol in 500mg launch pads. deuce techniques were apply so as to determine this-Extraction and purge of tab keys by filtration and recryst everyisation. -Hydrolysis of the drug under wane followed by titration against ammonium ion ion ion atomic number 58 sulfate.In addition to this, the truth of the paracetamol was investigated by role of campaigning destine of the respective brands of paracetamol.FindingsUsing the extraction and nicety summons it was strand that Tesco had the greatest comp unitynt by push- wad storage of the energetic ingredient, paracetamol, at 46.8%. Morrisons digs percentage by slew was 44.6% bandage Superdrug had a percentage by jam o f 37.8%.Using the wane and titration procedure it was implant that Superdrug had the greatest percentage by kitty of the active ingredient, paracetamol at 20.0%. The Tesco percentage by muddle was 19.6% while Morissons was 18.5%.The send away institutionalise procedure reason that all three cutting archetypes had similar purity of paracetamol with resolve point at 156oC. The warming point of the Morrisons recrystallised paracetamol was 168oC, Superdrug had a melting point of clxvoC while Tesco had a melting point of 164oC. This shows that Morrisons had the highest purity of slight paracetamol followed by Superdrug and and olibanum Tesco.Underlying Chemis depictHistory and UsesParacetamol (C8H9NO2) (or acetaminophen) is the virtually common over the counter painkiller in the world. It was discovered in 1852 by Charles Fredric Gerhardt who later went on to discover aspirin. The drug is so popular due to the a few(prenominal) berth effects it has on the body and does not irritate the stomach like other normally dod drugs such as aspirin. The structure is as shownParacetamol is apply for abatement of headaches, fever, menstrual pain, back pain, toothache and other general pain except it is ineffective against muscle pain as it possesses no anti-inflammatory properties. Non-opioid analgesics devise by inhibiting an enzyme known as cyclooxygenase (COX). COX is a gun for the conversion of a fatty window glass contained in cell wallsarachidonic acidulentto mental objects known as prostaglandins. (tuftsjournal.tufts.edu.) Prostaglandins have m all functions including the induction of pain. By cut back the production of prostaglandins the pain is relieved. Paracetamol does not strike the cause of the pain nevertheless rather combats the biochemical pathway which results in the feeling of pain.Prostaglandins in addition affect the hypothalamus in the brain, the centre which is responsible for the maintenance of our bodies internal environmen t notwithstanding channels to the external environment, i.e. homeostasis. The prostaglandins cause the body to raise its temperature, and hence by victorious paracetamol the body temperature is lowered. Paracetamol is therefore classed as antipyretic as it lowers the body temperature. referable to these properties the drug is commonly used to combat flu and shabby symptoms. The chuck of pain combatted by paracetamol alongside the fact that it has very few side effects has resulted in it universe the most commonly used painkiller.Paracetamol is in addition popular because of the rate at which pain subsides from its use due to the speedy uptake in the body. Absorption Rapidly and almost completely wrapped from the G.I. tract. Peak plasma dumbnesss are r all(prenominal)ed in 10-60 minutes.(labmed.yale.edu)MethodologyTwo techniques were used in the determination of the potbelly of active ingredient innovate in the tab keys. The first was the extraction and purification of p aracetamol from anovulatory drugs. The second was an acid catalysed hydrolysis under reflux followed by titrations against ammonium cerium sulphate.The use of the melting point pull up stakesed the purity of the paracetamol to be determined.The extraction and purification of paracetamolThis procedure extracted paracetamol from the tablets by crystallisation. The paracetamol tablets were crushed and mixture state in dimethyl ketone at a raised temperature this decreased the quantify needed for the paracetamol to dissolve. The binding agents and fillers in the tablet are water system-insoluble in dimethyl ketone however the paracetamol is soluble. This results in the paracetamol forming a base in the acetone while the other components of the tablet are left as insoluble residue. The solution was slavered to remove the residue. The filtrate was left to evaporate forming crystals of paracetamol.These crystals were then fade away in baking hot water and then driveled through cotton woollen to remove any binding agents left. This filtrate was left in the electric refrigerator and shards of paracetamol create. This relies on the fact that paracetamol has a high solubility in hot water but a low one in cold water. This allows shards of paracetamol to form. The soluble impurities are only present to the level of a few percent and so never reach their limit of solubility and and so stay in solution. (Ellis, 2002)The polished recrystallised paracetamol was then dried and its hole measured. The percentage by mass was then calculated. ebbing and titrationsThis procedure infallible the paracetamol to be turn under reflux for one hour with sulphuric acid. This acid catalysed hydrolysis broke down the paracetamol (an amide) into an amine (4-aminophenol) and a carboxylic acid (ethanoic acid.) The raised temperature was used so as thermally accelerate the reaction. The reaction is shown beneath(Overall reaction)This reaction mechanism may be entrap in the app kiboshix.The use of reflux apparatus ensured that the reaction vessel never boiled dry. This is because any vapour form from estrus in the reaction vessel was sour back into a liquid by condensation. The benefit of development a heating mantle was that it ensured that a constant temperature, heating the play furnish flask over a greater surface area.This procedure produced 4-aminophenol. This has a hydroxyl assemblage on degree Celsius 1 and an amine group on the carbon 1. Since the nitrogen is attached to only one carbon it is a primary amine. The 4-aminophenol can then be alter utilize ammonium cerium sulphate, involving the loss of hydrogen from the 4-aminophenol victimisation ferroin as an index finger. This produced iminoquinone. yet after all the 4-aminophenol has been oxidised will the cerium (IV) reagent oxidise the ferroin indicator from Fe2+ to Fe3+ (ferriin). (Ellis, 2002) This resulted in the comment win over from red to yellow, as the red ferro in is oxidised to ferriin which is blue. This is shown in the diagram below When mixed with the ammonium cerium sulphate this produced a yellow colour which indicated the end point of the titration.A titration was also carried out without the test material existence present and the leaving amongst the values with the test species present and absent accounted for the mass of paracetamol present. The difference in volumes of titre necessary for the colour change is this instant proportional to the mass of paracetamol present in the tablet (0.007560g per 1cm3 equivalent titre.) resolve PointBy measuring the melting points of the given formulations, the purity of the paracetamol was able to be determined. Melting point apparatus worked by heating the species in a capillary vessel tube which itself was inserted into a heating cease. By looking through a lens at the species, the moment at which the species melted could be seen and then at this moment the reading on the thermometer c ould be viewed.When a substance is heated, there is an increase in entropy as the species is thermally excited. If exuberant energy is put into the substance, it results in a change of state, in this teddy solid to liquid.The three brands of paracetamol melting points were measured for the tablet, the crude and the recrystallised samples. Pure paracetamol is a white crystalline solid which melts at 169-171oC. (Ellis 2002).The impurities in the samples lower the melting points. The sample which was closest to the given melting point represents the keenst sample of paracetamol.ProceduresThe Extraction and Purification of ParacetamolPlease note this experiment was carried out twice for each brand and an come taken. This was then duplicated so as to improve the reliability. (This is shown in results as the replicate.)Paracetamol was extracted from three brands of paracetamol Morrisons, Superdrug and Tesco. These procedures represent the procedure used for each brand.Two tablets were weighed exploitation a balance (accurate to 2 D.P.) then crushed using a plaster and pestle. The ground tablets were hardened in a beaker. 50cm3 of dimethyl ketone was measured using a pipette. The acetone was used to rinse off the mortar and pestle before adding it to the beaker. The beaker was left on a brisk bustle at a low heat until the tablet was dissolved as off the beaten track(predicate) as possible. The insoluble material was the binding agents and fillers. signly 20cm3 of propanone was used however it was undercoat that the tablets did not dissolve fully.A Buchner funnel was particularise up as shown (see left.)The insoluble material (binding agents and fillers) collects in the filter idea.The filtrate (propanone and paracetamol) is collected in the filtering flask.A little propanone was run through the filter paper so as to create a seal among the filter paper and the base as shown on the above diagram. This foiled the insoluble material from passing throu gh the holes in the funnel. The cloy of the beaker was passed through the funnel and a little propanone was used to rinse the beaker. The filtrate was left in an evaporating basin overnight in an oven. This formed crude paracetamol crystals. The mass of the crystals was taken.The crystals were placed in a beaker and 20cm3 of hot water was added. The beaker was heated on a brisk stir until the paracetamol had dissolved. This was passed through a warmed wet piece of cotton wool in a warmed glass funnel. This was to prevent the paracetamol from recrystallising in the cotton during filtration. The filtrate was passed directly into a basin. The basin was placed in the fridge overnight to still and to allow the crystals to form. These crystals were white.The recrystallised paracetamol in water was passed through a piece of fluted filter paper to collect the crystals. ( signly the paracetamol was filtered out of the water using a work glass crucible however this produced a lower yield as crystals were lost when using this technique. See table 22.) The filter paper and crystals were placed in an oven at room temperature overnight to allow the crystals to dry. These crystals were white. The dry mass of the crystals was measured. This procedure was replicated for each brand of paracetamol.Reflux and titrationsPlease note that this procedure was carried out once for each brand of paracetamol. This was then duplicated so as to improve the reliability. (This is shown in the results as the replicate.)The first stage of this procedure obscure the acid hydrolysis of paracetamol15cm3 of 2 molar solution of sulphuric acid and 25cm3 of water were measured using a pipette and placed in a atomic number 6ml round bottomed flask. To this 0.30g of crushed (using mortar and pestle) paracetamol tablet was added, having measured the paracetamol using a balance (accurate to 2 D.P.) This was swirled and warmed until the tablet was dissolved. This was then boiled under reflux for one hour in a heating mantle as shown belowThe paracetamol and sulphuric acid were placed nn the round bottomed flask.The solution turned from colourless to a light gold colour. The solution was cooled and vitamin Ccm3 of water was added.20cm3 of the resulting solution was pipetted into a conical flask with 15cm3 of 2 molar Hydrochloric acid, 40cm3 of water and precisely 8 drops of ferroin indicator. This was then titrated against 0.1 molar solution of ammonium cerium sulphate until colour changed from a pink/ yellowish pink colour to a cloudy yellow colour. (The colour change was not very obvious during this procedure. Therefore previous titration colours were kept beside the species to try to standardize the colour at which the end point of the titration was determined.) The titrations were perennial until two results were within 0.1cm3 of each other i.e. until two concordant results were obtained. The apparatus is as shown overleafThe burette was filled with the yellow ammonium cerium sulphate solution and the conical flask contained the paracetamol acid mixture.This procedure was also repeated without the test material present.Melting PointDuring this procedure, the melting points of the recrystallised, crude and unmoved tablet forms of paracetamol were investigated.The sample of species was crushed into a powder using a mortar and pestle. Capillary tubes (1mm diameter, 10cm long) were sealed at one end using a Bunsen burner. This provided a place to hold the paracetamol when using the melting point apparatus. The capillary tube was placed turned open-side-down and pressed onto the paracetamol formulations. because the closed end of the capillary tubes was gently tapped on the table to allow the paracetamol to fall to the closed end. This was then placed open-side-up into the metal heating block alongside a thermometer. The temperature was slowly change magnitude using the thermostat on the melting point apparatus while the paracetamol was viewed throu gh the magnifying glass on the apparatus. The point at which the paracetamol melted was then recorded.Results signExtraction and purificationThe crystals of the crude and recrystallised paracetamol were both white. The crude crystals were prismatic shaped while the recrystallised paracetamol formed long shards. dodge 1 shows the mass of crude paracetamol from each tablet card 1 brand battalion (g) standard 1 smack 2 honestTesco0.941.000.97Morrisons1.011.001.01Superdrug0.970.920.95 hold over 2 shows the mass of recrystallised paracetamol from each tablet flurry 2Brand push-down storage (g) attempt 1Sample 2 mean(a)Tesco0.580.490.54Morrisons0.440.490.47Superdrug0.360.480.42 knock back 3 shows the percentage by mass of crude paracetamol compared to the mass of two tablets (1.10g) evade 3Brand division of Crude Paracetamol (%)Tesco88.2Morrisons91.8Superdrug86.4(Calculations may be found in the appendix)Table 4 shows the mass of recrystallised paracetamol compared to the respective mass of two tablets (1.10g)Table 4Brand contribution of pure Paracetamol (%)Tesco49.1Morrisons42.7Superdrug38.2(Calculations may be found in the appendix)Reflux and titrationsTable 5 shows the volume of Ammonium atomic number 58 sulphate required for the colour change from red to yellow to go across without the test species present (paracetamol)Table 5Titrationinitial titre(cm3) closing Titre(cm3) mess of ammonium cerium (IV) sulphate needed for the colour change (cm3) testy0.00.50.5 head start0.51.00.5Second1.01.50.5 mean(a) Titre = (0.5+0.5)/2 = 0.5cm3Table 6 shows the volume of Ammonium atomic number 58 sulphate required for the colour change from red to yellow to decease using Tesco paracetamolTable 6Titration sign Titre(cm3)Final Titre(cm3)Volume of ammonium cerium (IV) sulphate needed for the colour change (cm3)Rough0.08.68.6 initiatory8.615.87.2Second15.823.17.3Average volume = (7.2+7.3)/2 = 7.25cm3amend titre = 7.25-0.5 = 6.75cm3As 1 cm3 of ammonium cerium (IV) sulphate = 0.007 560g of Paracetamol6.75 x 0.007560 = 0.05103gSo, if 0.3g of tablet 0.05103g of pure ParacetamolThen, 0.55g of tablet 0.093555g of pure ParacetamolPercentage by mass (0.093555/0.55) x 100 =17.0%Table 7 shows the volume of Ammonium Cerium sulphate required for the colour change from red to yellow to occur using Morrisons paracetamolTable 7TitrationInitial Titre(cm3)Final Titre(cm3)Volume of ammonium cerium (IV) sulphate needed for the colour change (cm3)Rough0.07.47.4First7.414.47.0Second14.421.57.1Average volume = (7.0+7.1)/2 = 7.05cm3amend titre = 7.05-0.5 = 6.55cm3As 1 cm3 of ammonium cerium (IV) sulphate = 0.007560g of Paracetamol6.55 x 0.007560 = 0.049518gSo, if 0.3g of tablet 0.049518g of pure ParacetamolThen, 0.55g of tablet 0.090783g of pure ParacetamolPercentage by mass (0.090783/0.55) x 100 =16.5%Table 8 shows the volume of Ammonium Cerium sulphate required for the colour change from red to yellow to occur using Superdrug paracetamolTable 8TitrationInitial Titre(cm3)Final Ti tre(cm3)Volume of ammonium cerium (IV) sulphate needed for the colour change (cm3)Rough0.09.79.7First9.718.68.9Second18.827.89.0Average volume = (8.9+9.0)/2 = 8.95cm3Amended titre = 8.95-0.5 = 8.45cm3As 1 cm3 of ammonium cerium (IV) sulphate = 0.007560g of Paracetamol8.45 x 0.007560 = 0.063882gSo, if 0.3g of tablet 0.063882g of pure ParacetamolThen, 0.55g of tablet 0.117117g of pure ParacetamolPercentage by mass (0.117117/0.55) x 100 =21.3%Table 9 shows the melting points of the paracetamolTable 9BrandMelting Point (0C) domiciliation SampleCrude SampleRecrystallised SampleTesco140155163Morrisons cxlv157167Superdrug139159164ReplicateExtraction and purificationThe crystals of the crude and recrystallised paracetamol were both white. The crude crystals were prismatic shaped while the recrystallised paracetamol formed long shards.Table 10 shows the mass of crude paracetamol from each tabletTable 10BrandMass (g)Sample 1Sample 2AverageTesco1.000.980.99Morrisons1.001.041.02Superdrug1.010.9 70.99Table 11 shows the mass of recrystallised paracetamol from each tabletTable 11BrandMass (g)Sample 1Sample 2AverageTesco0.510.460.49Morrisons0.530.490.51Superdrug0.400.420.41Table 12 shows the percentage by mass of crude paracetamol compared to the mass of two tablets (1.10g)Table 12BrandPercentage of crude Paracetamol (%)Tesco90.0Morrisons92.7Superdrug90.0(Calculations may be found in the appendix)Table 13 shows the mass of recrystallised paracetamol compared to the mass of two tablets (1.10g)Table 13BrandPercentage of pure Paracetamol (%)Tesco44.5Morrisons46.4Superdrug37.3(Calculations may be found in the appendix)Reflux and titrationsTable 14 shows the volume of Ammonium Cerium sulphate required for the colour change from red to yellow to occur without the test species present (paracetamol)Table 14TitrationInitial Titre(cm3)Final Titre(cm3)Volume of ammonium cerium (IV) sulphate needed for the colour change (cm3)Rough0.00.50.5First0.51.10.6Second1.11.60.5Average volume = (0.5 +0.6)/2 = 0.55 cm3Table 15 shows the volume of Ammonium Cerium sulphate required for the colour change from red to yellow to occur using Tesco paracetamolTable 15TitrationInitial Titre(cm3)Final Titre(cm3)Volume of ammonium cerium (IV) sulphate needed for the colour change (cm3)Rough0.010.610.6First10.620.09.4Second20.029.39.3Average volume = (9.3+9.4)/2 = 9.35cm3Amended titre = 9.35-0.55 = 8.8cm3As 1 cm3 of ammonium cerium (IV) sulphate = 0.007560g of Paracetamol8.8 x 0.007560 = 0.066528gSo, if 0.3g of tablet 0.066528g of pure ParacetamolThen, 0.55g of tablet 0.121968g of pure ParacetamolPercentage by mass (0.121968/0.55) x 100 =22.2%Table 16 shows the volume of Ammonium Cerium sulphate required for the colour change from red to yellow to occur using Morrisons paracetamolTable 16TitrationInitial Titre(cm3)Final Titre(cm3)Volume of ammonium cerium (IV) sulphate needed for the colour change (cm3)Rough21.530.59.0First30.539.59.0Second39.547.68.1Third0.008.68.6Fourth8.617.38.7Average v olume = (8.7+8.6)/2 = 8.65cm3Amended titre = 8.65-0.55 = 8.1cm3As 1 cm3 of ammonium cerium (IV) sulphate = 0.007560g of Paracetamol8.1 x 0.007560 = 0.061236gSo, if 0.3g of tablet 0.061236g of pure ParacetamolThen, 0.55g of tablet 0.112266g of pure ParacetamolPercentage by mass (0.112266/0.55) x 100 =20.4%Table 17 shows the volume of Ammonium Cerium sulphate required for the colour change from red to yellow to occur using Superdrug paracetamolTable 17TitrationInitial Titre(cm3)Final Titre(cm3)Volume of ammonium cerium (IV) sulphate needed for the colour change (cm3)Rough0.08.38.3First8.316.27.9Second16.224.28.0Average volume = (7.9+8.0)/2 = 7.95cm3Amended titre = 7.95-0.55 = 7.4cm3As 1 cm3 of ammonium cerium (IV) sulphate = 0.007560g of Paracetamol7.4 x 0.007560 = 0.055944gSo, if 0.3g of tablet 0.055944g of pure ParacetamolThen, 0.55g of tablet 0.102564g of pure ParacetamolPercentage by mass (0.102564/0.55) x 100 =18.6%Table 18 shows the melting points of the paracetamolTable 18Brand Melting Point (0C)Tablet SampleCrude SampleRecrystallised SampleTesco143156165Morrisons144155168Superdrug141153166Averages of Initial and replicateTable 19 shows percentage by mass of recrystallised paracetamolTable 19Percentage by mass%BrandInitialReplicateAverageTesco49.144.546.8Morrrisons42.746.444.6Superdrug38.237.337.8Table 20 shows percentage by mass of pure paracetamol determined from reflux and titrationsTable 20Percentage by mass %BrandInitialReplicateAverageTesco17.022.219.6Morrisons16.520.418.5Superdrug21.318.620.0Table 21 shows the melting point of paracetamol of crude and recrystallised paracetamolTable 21Melting point (oC)CrudeRecrystallisedBrandInitialReplicateAverageInitialReplicateAverageTesco155156156163165164Morrisons157155156167168168Superdrug159153156164166165Table 22 shows the results using a forge glass crucible rather than filter paper during the filtration of Tesco recrystallised paracetamolTable 22Sample 1Sample 2Mass of crystals (g)0.310.12ConclusionsThe aim of this investigation was to determine the percentage by mass of pure paracetamol in formulations of branded paracetamol in 500mg tablets. Two techniques were employed so as to determine this-Extraction and purification of tablets by filtration and recrystallisation. -Hydrolysis of the drug under reflux followed by titration against ammonium cerium sulphate.In addition to this, the purity of the paracetamol was investigated by determination of melting point of the respective brands of paracetamol.The results of these procedures are discussed below.Extraction and purificationUsing this procedure it was found that Tesco had the greatest percentage by mass of the active ingredient, paracetamol, at 46.8%. Morrisons tablet percentage by mass was 44.6% while Superdrug had a percentage by mass of 37.8%.Reflux and TitrationsUsing this procedure it was found that Superdrug had the greatest percentage by mass of the active ingredient, paracetamol at 20.0%. The Tesco percentage by mass was 19.6% while Morissons was 18.5%.Results were opposite for each respective brand of paracetamol and different between the two procedures.Melting PointThe melting points of the crude paracetamol were all 156oC thus showing that all formulations of crude paracetamol had similar purity, and hence the first quartz glass of the paracetamol was carried out very accurately.The melting point of the Morrisons recrystallised paracetamol was 168oC which compared well with the given melting point of 169-171oC. Superdrug had a melting point of 165oC while Tesco had a melting point of 164oc. This shows that Morrisons had the highest purity of pure paracetamol followed by Superdrug and then Tesco. evaluationEvaluation of proceduresControl of variablesDuring the filtration and recrystallising process two tablets were used in each sample and two samples were taken. This, alongside the duplication of results, gives 8 tablets which were used in the determination using this method and an average take n. This increased the reliability of the results.During the procedures the same balances, burettes, flasks and pipettes were used so as to reduce the effects of error in these measurements.When titrations were carried out, a rough titration was initially done so as to determine the equivalence point. This was followed by accurate titrations. When two concurrent values were within 0.1cm3, an average was taken between these two values. The average was used to determine the mass of pure paracetamol greatly increasing the reliability of the results.Since the end point of the titration was not very obvious, previous titrations were kept aside so as to assess the intensity of yellow in the solution, so that all titrations had the same end point colour. This increased the reliability of the titrations.All equipment used was cleaned using propanone to prevent chemicals from previous experiments contaminating this investigation. In addition to this the burettes and pipettes were rinsed wit h the solutions, before being filled with the same solution to prevent contamination.When using the balance, as far as possible, it was placed away from draughts and windows so as to prevent the wind causing error in the weighing of substances.Where possible, all reaction vessels and weighing receptacles were rinsed using a little of the liquid which would be used. This increased the yield of results, preventing the reactants being lost in the process.ModificationsInitially, when dissolving the paracetamol in propanone, the tablet was not crushed however it took an inordinate time for the tablet to dissolve by the time it had dissolved most of the propanone had evaporatedThe volume of propanone was increased from 20cm3 to 50cm3 because more paracetamol dissolved. This allowed a greater percentage of the paracetamol to be extracted from the tablets. consequentially it took longer for the crude paracetamol crystals to form.Initially a sintered glass crucible was used to filter the rec rystallised paracetamol. This resulted in the paracetamol being lost, so filter paper was fluted and used instead. This resulted in a greater mass of recrystallised paracetamol being collected.When the paracetamol was being added to sulphuric acid, initially it was unheated and just swirled, however not all the paracetamol dissolved and hence, the sulphuric acid was warmed with the paracetamol to dissolve the crushed tablet before being boiled under reflux.When using the ammonium cerium (IV) sulphate, it was found that if left for any length of time greater than one hour the solute came out of solution, therefore, before pouring the solution into the burette, it was stirred cleverly using a magnetic stirrer to ensure the same concentration of solution was used in every titration. Because of this, the burette was only set up immediately before use.Evaluation of resultsBoth procedures resulted in significantly lower percentages than the mass of paracetamol in each tablet as verbali ze on the box. The expected percentage by mass was expected to be 90.9%. This is calculated as shownMass of tablet 0.55g Mass of paracetamol (on box) 0.50g(0.5/0.55) x 100 = 90.9%Generally the replicate compared well with the initial experiment, with a maximum difference of 4.6% by mass for the first procedure. For the second procedure there was a maximum difference of 5.2% by mass. This can be put down to errors in the equipment and human errors when carrying out procedures.The fact that both procedures indicated different formulations contained the most paracetamol, may be due to the fact that often paracetamol was taken from different blister packs, and hence from different batches, which may contain different sight of paracetamol. However human errors and errors in equipment are more likely to be to blame.It can also be broadly sai