For many grounds, this path was assumed suboptimal as a commercial fabrication for illustration ; it is additive with nine stairss, sulphonyl chloride, which is one of the toxic substances produced from this path is in the concluding bond-forming reaction. Concluding stuff required a batch of recrystallizations to cut down the toxic drosss to suitably low degrees in order to bring forth the high quality of drug required by pharmaceutical company. Due to viing hydrolysis through the increased satisfied times on scale-up chlorosulphonation in chemical development ; the troubles of scaling-up reactions are well-known.
In this path, 2-pentanone and diethyl oxalate are condensed to give the diketoester 1. Then, cyclizating the diketoester by hydrazine green goodss pyrazole 2 which methylated with selective to give pyrazole3. Hydrolyzing the reaction generated the acid 4, so convert acid to the amide by nitration to give nitropyrazole 5, which is common intermediate in all man-made paths. Decrease of 5 with Sn ( II ) chloride dehydrate to give the aminoalkane 6 which is by 2-ethoxybenzoyl chloride was acylated to bring forth diamide 7. The later was cyclized utilizing aqueous Na hydrated oxide and H peroxide to ensue in 8 pyrazolo [ 4,3-d ] pyrimidin-7-one. Sildenafil was produced by selective chlorosulfonation and reaction with N-methylpiperazine. ( 6 )
Optimization of the cyclization reaction to do the pyrimidinone was the cardinal determination during the development of the medicative chemical science path, which impacted on the programme as a whole. Cyclization of compound 4 was done by Na hydrated oxide and H peroxide, which are an aqueous alcoholic solution and lead to moderate output ( 30-70 % ) . The hydrolysis of the carboxamide to give the acid either in the presence or absence of the H peroxide was the chief side merchandise from the medicative reaction. To avoid the hydrolysis side merchandise, cyclization was conducted under anhydrous conditions, KOtBu/ButOH and the reaction continued in 100 % merchandise without detected drosss. By sing reordering the stairss, the clean cyclization was the concluding bond-forming reaction. ( 1 )
Alteration of the medicative path:
A batch of alterations were applied into medicative chemical science path, which was used at the beginning of the undertaking to fix 50 kgs and support supply for the four old ages. ( 6 )
For early scale-up, the Sn ( II ) chloride decrease was removed. Tin is major environmental defiler and a heavy metal. It was replaced with a catalytic hydrogenation. At the early age of the Viagra production, a Sn chloride decrease was employed because the hydrogenation decrease was non in operation. The ground for inefficient of the hydrogenation was a presence of hint degrees of S drosss which poison the hydrogenation reaction. Switch overing to stoichiometric thionyl chloride is one illustration that controlled sulfur drosss and allows the dependability of the catalytic hydrogenation reaction. Using a hydrogenation, there are options for dissolver and accelerator recovery and H2O is the lone byproduct. ( 5 )
Hydrogen peroxide was used in cyclization method to change over 7 to 8, but it causes skin Burnss. Furthermore, in contact with organic stuffs, it is a fire and transit risky. Then, it was replaced with KOtBu/ButOH. Rather than utilizing oxalyl chloride, thionyl chloride is used to fix 2-ethoxybenzoyl chloride which eliminates exposure to carbon monoxide emanations by workers. ( 5 )
Through formation of pyrazole 3 which is an exothermal reaction, a dissolver was introduced. Furthermore, for 5 readyings, methylbenzene was introduced as a dissolver which reduces the degree of thionyl chloride from 1.6 to 1.8 equivalents. ( 6 )
The mark from Sildenafil citrate was for intervention of angina when entered development. But the clinical consequences were failed. Pfizer made a test with 12 patients tolerate from male erectile disfunction in 1994. The consequences showed betterments in the jobs of 10 patients. As a effect, sildenafil citrate development became one of the highest precedences in the Pfizer portfolio ( 6 ) .
There are many advantages of commercial path over the optimized medicative one, for illustration ;
-The synthesis was redesigned to do convergence.
-The concluding bond forming measure is the clean cyclisation reaction and at the start of the synthesis, the potentially toxic stuffs occur.
-Large volumes of aqueous acidic waste require an increased degree of hydrolysis and neutralisation through a larger graduated table is an illustration of environmental and scale-up issues associated with chlorosulphonation reaction. In order to cut down these issues, they are placed at the start of the synthesis. Hence, low molecular weight and cheaper stuffs are used. ( 5 ) .
Through pyrazole 5, many paths of synthesis proceeded.
Using chlorosulfonic acid, 2-ethoxybenzoic acid is Chlorosulfonated by utilizing 1 mol of thionyl chloride to change over the intermediate sulfonic acid to the sulfonyl chloride. Due to moo runing point of 2-ethoxybenzoic acid ( 19-20 C ) military policeman, low molecular volumes of chlorosulfonic acid and thionyl chloride are used and therefore no solubilisation. Initially, the sulfa drug 9 was isolated as unusual dual salt 10 which is indissoluble and hard to utilize. Furthermore, in order to obtain the dual salt to crystallise, the sulphonyl chloride should be dry which lead to a batch of acidic, caustic exhausts in a pilot works graduated table. Then, it was discovered that 9 can be isolated as its extremely crystalline zwitterions by intervention the dual salt with H2O to disassociate and bring forth a new signifier of free crystalline amino acids 8. For efficiency, the sulfonyl chloride was converted to sulfonamide 9 by resuspended in H2O and reaction with N-methylpiperazine. At the terminal of the reaction, by the add-on of aqueous Na hydrated oxide, the pH was adjusted to the isoelectric point and the precipitated compound 8 collected by filtration. As a consequence, during sulfonamide readying, no organic dissolvers are used.
Hydrogenation and matching reaction:
In medicative chemical science, the Sn ( II ) chloride decrease was replaced by a Pd catalyzed hydrogenation reaction to change over pyrazole 1 into the amide2. Toluene was introduced as a heat dissolver which increased the safety of the procedure and reduced the degrees of thionyl chloride to 1.2-1.6 equivalents. To change over the nytropyrazole ( 2 ) to the aminoalkane ( 3 ) heterogenous hydrogenation in ethyl ethanoate was used. A figure of reagents, including thionyl chloride, oxalyl chloride and N, N-cabonyldiimidazole ( CDI ) are used to analyze the activation of the carboxylic acid.
CDI costs around 8 $ /mol and supply such advantages for cases ; high quality merchandise, robust and clean chemical science. Furthermore, it provided a combination of the three reactions ( hydrogenation, acerb activation and acylation ) into a individual measure, employed the ethyl ethanoate dissolver with a simple recovery procedure and used low energy. In add-on, VOC emanations were avoided such as ( EtCl ) that generated from the interaction of ethyl chloride with thionyl chloride or oxalyl chloride. Furthermore, 90 % chemical output over three chemical reactions is produced and optimized to 96 % .
Cyclisation Chemical reaction:
The resulting merchandise is heated for several hours and cyclised with 1.2 equivalents of K t-BuOH and t-BuOK. In order to minimise the environmental wastes, this procedure is run at high concentration ( 2.5-3.75L Kg-1 ) . Water is added to thin the reaction and the pH was adjusted with 4M HCl to the isoelectric point ( 7.5 ) . Clinical really high quality output of 95 % Viagra was obtained by filtration. Using 2-butanone citric acid, Viagra was converted to sildenafil citrate to give a output of 99 to 100 % .
History of Sildenafil:
Initially Viagra was developed to handle angina ( bosom disease ) . In Morriston infirmary, the drug was tried on work forces in 1991-1992. The clinical observation showed that the drug enhance penile hard-on more than handling angina. Pharmaceutical company, Pfizer commercialized the drug as a intervention for erectile disfunction. In 1996, the drug was patented and approved on 27 March 1998 by FDA. It was the first sanctioned drug for penial hard-on in the United States and the gross revenues exceed 1 $ billion in 1999-2001. The Pfizer ‘s patents on this drug will run out in 2011-2013.
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Dose of Viagra:
Viagra could be taken one time per twenty-four hours as a dosage between 25mg to 100mg between 30 min to 4 hours before sexual intercourse. Three doses are available in market for this drug ( 25-50-100 ) milligram with a cost of 10 $ per pill for all doses.
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Mode of action:
Effectss on Penile Erection:
Sildenafil citrate is a selective inhibitor of phosphodiesterase-5 ( PDE5 ) and was used for the intervention of the male erectile disfunction ( known as powerlessness ) . It is a broad spread status that effects around 30 million patients in United States. Nitric oxide is released during sexual stimulation and permeates through principal cavernosum membranes. Then, the enzyme guanylate cyclase is stimulated to heighten degrees of cyclic guanosine monophosphate ( cGMP ) in the principal cavernosum. cGMP has an effects on smooth musculus relaxation and increases blood flow lead to an hard-on of the phallus. Degree of PDE5 is high in the principal cavernosum which hydrolyzes cGMP and leads to inactive GMP. Levels of cGMP in work forces with powerlessness are low and as a effect PDE5 rapidly hydrolyses these degrees of cGMP. Now, the Viagra Acts of the Apostless by suppressing the actions of PDE5 and increases the degrees of cGMP which cause the hard-on. ( 6 ) figure involved
Sildenafil binds to PDE5 and blocks action
Effectss on Ocular Function:
In patients taking Viagra, it has been reported such ocular abnormalcies for illustration ; increased blurred vision and perceptual experience of visible radiation. These effects normally happened with dosage more that 100mg which is correlated to the weaker suppression effects of Viagra on PDE6 that regulates signal transduction tracts in the retinal receptors. ( 2 )
Sidenafil has effects on blood force per unit areas by bring forthing transeunt decrease in systolic and diastolic at 1 hr after the dosage. The clinical trials showed no ascertained effects on bosom rate. Sildenafil effects are non age or dose dependant. ( 2 )
The Viagra was tested in vitro to analyze the suppression of PDE5 in human blood thrombocytes. The consequences showed the authority of Viagra and it is a selective inhibitor of both hundred GMP PDEs. Besides, a figure of tests were carried on coney principal cavernosum to analyze the consequence on the musculus. From the consequences, appear that Viagra was powerful in loosen uping the principal cavernosum. Furthermore, to measure smooth musculus relaxation, set of experiments were carried in coney stray aortal rings. Sildenafil showed similar values in both bald and endothelial integral aortal rings. ( 28 )
Side Effectss from Clinical surveies:
Patients having Viagra showed similar inauspicious effects in all tests. Some surveies showed more effects with increased dosage. There were some inauspicious events reported when Viagra is taken in flexible dosage for illustration ; concern, roseola, giddiness, diarrhoea, urinary piece of land infection, flushing, indigestion and rhinal congestion.
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Pharmacokineticss and Metamorphosis:
The cytochrome P450 3A4 metabolizes sildenafil which alterations to an active N-desmethyl metabolite that has the 50 % activity of the drug for suppressing PDE5. This metabolite has 40 % plasma concentrations of Viagra, therefore it possess 20 % of the pharmacological effects of Viagra. Terminal half-lives of Viagra and its metabolite are 4 hours each. Sildenafil distributed into the tissues with a volume of 105 L and excreted in the fecal matters as metabolites. In patients aged & amp ; gt ; 65 old ages, plasma degrees increased every bit good in patients suffered from hepatic damage and nephritic damage. ( 2 )
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Sildenafil citrate which is the active pharmaceutical ingredients for Viagra was manufactured by Pfizer at Ringaskiddy and the entire end product from Viagra gross revenues was history for 15 % . The installation covers 200 estates and composed of four production units with 500 people working at that place. OSP4 is the chief works at Ringaskiddy that addition production by 40 % and started in 2001.
Construction of the new man-made works ( OSP4 ) , a finished good edifice ( FGB ) and all other services were under duty of Project Management and Foster Wheeler. Plant started fabricating in March 2001. Planing installation enable the OSP4 works to bring forth primary majority, batch pharmaceutical merchandises at a reactor of 150,000 litres and six lines are at full graduated table. To increase service of OSP4, Pfizer was be aftering to construct a 3rd liquid waste incinerator.
At the works, the manufactured merchandises are either bulk active or drug substances. For the majority stuffs, they are sent in order to finish preparation and bundle for transportation.
Production and works installation:
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For all drugs, ab initio they are produced in little a saddle horses for the probe and in vitro analysis. Then, measures are increased if the carried trials are successful to run into the demands for clinical tests and patients.
For the first clip, production of one kilogram of Viagra requires a series of 11 reactions with 23 kilograms of reagents and 139 litres of organic wastes. All readyings are carried in a microwave designed particularly for organic chemical science.
For scaling up the procedure, it has to be more efficient and consequence in fewer wastes. Presently, in Viagra production merely 1.5 kilograms of reagents are used and let go of merely 10 litres of wastes. The company purpose to minimise the waste to 6 L per kg produced. Now, every twelvemonth the demand is 45 tones for good quality Viagra in compared to 1998 where the cubic decimeter kilogram production was adequate for people demands in 10 proceedingss. To scale up reaction, all get downing stuffs were available commercially and used without purification. Using a microwave oven ETHOS 1600, synthesis was performed. In standard Pyrex glasswork, all reactions were carried out with a reflux capacitor. The reactions were performed by a plan which made up of temperature monitoring and keeping stairss. Purity of the concluding merchandise was measured utilizing thin-layer chromatography and molecular weight was recorded by electrospray ionisation mass spectroscopy. sealed vass are used which controlled and monitored by computing machines to do the needed measures of pure drug. Pipes are used to add the reagents into the vas and the merchandises are reaping later on. Control panels are applied that allow the operator to do any needed accommodations and supervising the procedure. A microwave-transparent fluoroptic investigation that inserted into the solutions was used to supervise the temperature of the moved reactions mixture. To bring forth any pharmaceuticals, highest criterions of hygiene are necessary and Laboratory should be clean and tidy.
Misuse of Viagra in Asia:
hypertext transfer protocol: //www.ergogenics.org/138.html ( faked drug )
Harmonizing to World Health Organization ( WHO ) , one of the most counterfeited drugs in Asia is Viagra which make a large concern. Tourists in Thailand use sham Viagra which is bought over legion pharmaceuticss. Therefore serious wellness hazards affected those tourers. Counterfeited medical specialties can enforce the right ingredients but bogus bundle, or without active ingredients, incorrect ingredients or with deficient active ingredients. Fake Viagra made up of ingredients that enhance the organic structure ‘s insulin production which can do a danger bead in the concentrations of blood glucose. As a consequence lead to hungering the energy of encephalon which in known as insulin daze syndrome. There is a widespread smuggling of sham and echt Viagra in Thailand harmonizing to A Thai Food and Drug Administration ( FDA ) . Unsurprisingly, Thailand is a Centre for bogus Viagra. Among immature night-clubbers, Viagra is blending with other party drug to increase the sexual desire.
There were alternate medicines prescribed for erectile disfunction prior to the debut of Viagra. Most of them are non-oral interventions. For illustration ; the primary options in the United States were vacuum bottleneck devices, penial injection therapy, penile prosthetic devices, professional guidance and transurethral. Traditional redresss were used in other states such as yohimbine. ( 4 )
Viagra Gross saless around the universe:
First, after FDA granted blessing of Viagra, it was sold in the United States. Nowadays more than 50 states are selling Viagra in their pharmaceuticss. On the U.S. market, one month after launch, the worth of gross revenues was 400 $ million which consequence from 300,000 Viagra prescriptions. Since so, 7 $ per tablet was maintained by Pfizer. The mean sweeping monetary value is 8.75 $ per pill in comparison with other interventions such as ; Caverject and Muse which priced at 20-30 $ per pill. Furthermore, gross revenues in most European states began shortly in September 1998 after European Medicines Evaluation Agency ( EMEA ) granted European states the enrollment for Viagra utilizations. In the United Kingdom, Sweden and democracy of Ireland, the authorities Health System covers the purchases of Viagra for limited utilizations. Public consciousness have been increased and focused on the safety issues in work forces taking Viagra and take to restrict the usage of Viagra after studies over deceases and inauspicious effects that were sent to the FDA. U.S. and most other states experienced prescription leveling off after information gained by people used the drug. Most of them were non really suffer from erectile disfunction. After drug ‘s blessing in the United States, Latin America launched the drug. Then, Viagra was available in a figure of Asiatic states, New Zealand, Australia and Canada. In 1999, Japan approved drug ‘s utilizations after it accepted from other states the clinical tests informations for the first clip. ( 4 )
In the medicative path, there are a figure of organic dissolvers included in the production of 1000 kilogram of drug substance and the volume of these dissolvers equal to 125,000 litres. These dissolvers are reduced to 13,500 litres in the commercial path. The dissolvers required in both paths are illustrated in figure 1.
Organic wastes from medicative path
Organic wastes from commercial path
For environmental appraisal, the decrease of some dissolvers for illustration ; chlorinated dissolvers and extremely volatile dissolvers such as ; methyl chloride, methyl alcohol, propanone and diethyl ether. Elimination of these dissolvers consequences in riddance of atmospheric emanations. T-butanol that has been used in the commercial path is wholly H2O soluble and is hard for reuse. In order to better environmental public presentation, t-buanol is replaced by another dissolver to ease recovery. The optimized procedure was developed in Ringaskiddy and will be used in the production works which will give 4 fifty kg-1 of the concluding optimized dissolver use. ( 5 )
hypertext transfer protocol: //en.wikipedia.org/wiki/Atom_economy
Atom economic system is the efficiency of transition all reactants in a chemical procedure in a manner of all atoms involved and no atoms are wasted. All starting stuffs equal to generated procedure, this represent an of import construct in green chemical science. Reaction mass efficiency is a step for the consequence of output and an addition of used reagents.
Between 1994 and 1997 where the new commercial path was introduced, there was an betterment in the reaction mass efficiency and chemical outputs. In contrast, the atom economic system remained invariables over clip. Comparisons of these parametric quantities between 1994 and 1997 is shown in figure
Fig. Atom economic system, chemical output and RME at 1994, 1997 and the hereafter mark in the sildenafil citrate procedure.
The aqueous and organic wastes are really measured and from patterning procedure the atmospheric emanations are estimated. There was a big decrease in the aqueous waste when the commercial path was introduced into the production. Furthermore, upon debut of the commercial path, once more there was a noticeable decrease in the organic wastes between 1994 and 1997. Due to the impact of presenting solvent recovery operations and reuse in the fabrication procedure, a farther big decrease occurred after 1997. These diminishing reflect the importance of extinguishing wastes and commanding path choice. For the vapour emanations, there have been smaller diminish in the released sum. In add-on, it was found at that place was 35 % lessening in the estimated energy used between 1994 and 1997. There are two grounds behind smaller decrease in the vapour emanations and the used energy ; foremost, in order to maximise the output, there is a important degree of dissolvers depriving performed in the commercial procedure. Secondary, the chemical science squad actively managed and followed such parametric quantities for case ; organic, aqueous wastes and output. On the other manus, they calculated retrospectively the emanations and energy. ( 5 ) Figure shows the comparings between these wastes at assorted times.
The E-factor is the entire kg of wastes per kg of merchandise. In commercial path of Viagra production, the E-factor is 6 kilogram kg-1 which is less than the industry criterion of ( 25-100 ) ( 6 )
Low volumes of the complicated chemical merchandises and the E-factor of the commercial path for Viagra production generate fewer wastes per twelvemonth. For all of the environmental consciousness taken by Pfizer for the sildenafil citrate procedure, UK Award was granted to this company in 2003. ( 2 )
Harmonizing to the U.S. Patent and Trademark Office, patent for Viagra by Pfizer will run out on March 27, 2012. Then, a inexpensive generic version of the blockbuster erectile disfunction drug will be sold by any drug company. This will let more competition between Pfizer ‘s Viagra and the new generic versions and more options with cheaper monetary values for patients. Pfizer has three options to remain in the Viagra ‘s market. First, it can market itself as the chief company for selling Viagra, taking into history there are over 25 million work forces used its version and they don & amp ; acirc ; ˆ™t like to alter. Secondary, it can use for Viagra with FDA for OTC ( nonprescription ) . Finally, while bring forthing an upgraded version of Viagra which will go on keeping value of the patented merchandise, it can licence the original formula to Viagra to other companies.
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Alternate Paths to Sildenafil:
There are more than 15 different paths have been reported in the chemical and patent literature to sildenafil. Pfizer examined two chief options during the development procedure either by synthesis Viagra through the aldehyde 11 to bring forth dihydrosildenafil 12 so oxidise the merchandise or by the aura derived functions for illustration 13 or 14.
52 % of Viagra yielded from condensation between aldehyde and aminopyrazole to give dihydrosildenafil by adding an azeotropic distillment to take the H2O by merchandise. The output can be increased to 95 % as shown by some workers. ( PATENT 22918 )
Aldehyde Amine Dihydrosildenafil
Oxidation of dihydrosildenafil either by utilizing Na H sulphite ( NaHSO3 ) or utilizing little measure of trifluoroacetic acid and Pd/C at high temperature generated a good output of drug ( patent WO 01-98303 ) .
Combination between a nucleophilic supplanting reaction that uses ethanol as a dissolver and a hindered alkoxide ( KOBU ) or ethoxide ( EtOH ) as a base and the cyclization reaction which uses a compound like aura derived functions is another possible synthesis for Viagra. The combination reaction works for both cyclisation compounds, but by utilizing a compound where ( x= F ) the output from combination is 100 % . The usage of the chloro-series compound ( x=cl ) in the cyclisation reaction is better because of 2-chlorobenzoic acid is cheaper than 2-ethoxybenzoic acid. ( Patent figure EP 0994 115 )
Figure ( 13, 14, synthesis )
Halo Derived functions
X= Fe, yield= 100 %
In the terminal, all of these alternate paths were put on clasp due to the high efficiency of the commercial path and the clip force per unit areas of the development plan.
( 6 )
( 3 )
In the WO Patent ( 98284 ) , amidine 10 or iminoether 11 can be used in order to construct pyrimidine ring ( Viagra ) . By a Pinner reaction, the iminoether is made from the cyanide.
Amidine is made by reaction of the cyanide with chloromethylaluminium amide which is synthesized from trimethyl aluminum ( Me3Al ) and ammonium chloride ( NH4Cl )
Intermediate 14 was prepared from reaction of the acerb intermediate 13 with thionyl chloride ( SOCl2 ) to give the lactone which so can be reacted with ammonium hydroxide ( NH3 ) and ( EtOH ) to bring forth the pyrazolopyrimidinone which is off to do Viagra.
Acid intermediate Lactone
( Patent EP 1 002 798 ) Viagra synthesis from intermediate ( 6 ) , can be done by chlorosulphonate the intermediate 16 and before cyclisation the intermediate convert to the sulphonamide6.
There are many patents activities in bring forthing nonintersecting synthesis of sildinafil. Workers at the Torcan Company reduced Carbamate by ( LiALH4 ) to sildenafil in ayield of 61 % . ( Patent 2 235 642 ) .
Besides, Viagra was synthesized from pyrazolopyrimidinone and the sulphamoyl chlorid ( which is prepared by SO2Cl2 and N-methylpiperazine reaction ) utilizing Friedel-Craft reaction which requires ALCl3 by workers at the India Orchid company. ( Patent EP 1 077 214 )
Pyrazolopyrimidine and sulphamoyl chloride Sildenafil
Furthermore, workers in Cipla Company have synthesized Viagra by dual methylation of this intermediate by utilizing formic acid and methanal ( CH2O ) and ( HCO2H ) as the concluding measure. ( Patent WO Patent 01/ 19827 )