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Manufacture of Fluconazole

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Manufacture of Fluconazole

Chapter 1 Introduction
Fluconazole is an antifungal triazole drug used in treatment of superficial and systemic fungal infections. In a bulk powder form,it appears as a white crystalline powder. Its very slightly soluble in water and soluble in alcohol. Its commonly marketed under the trade names Diflucan and Trican. (Source: M P Biomedicals)

Formula: C13 H12 F2 N6 O Molecular Mass : 306.271 g/mol. Structure:

(Source:Murthy et al.,1996)

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Manufacture of Fluconazole

Fluconazole was invented by Ken Richardson and received patent number 4404216 on September 13, 1983.It is a second generation triazole derivative and has been found to be efficacious against a host and of fungal ailments like mucocutaneous pulmonary

candidiasis,oropharangeal cryptococcosis,etc.

esophageal

candidiasis,isolated

Fluconazole is also found to act against following fungal species: Blastomyces dermatitidis, Histoplasma capsulatum ,Candida spp. (except C.krusei and C.glabrata), Coccidioidesimmitis ,Trichophytonspp. ,Cryptococcus neoformans ,Epidermophyton spp.

(Source:M P Biomedicals Longley et al.,(2008). Pfizer Australia Pty Ltd. Diflucan (Australian Approved Product Information). West Ryde (NSW): Pfizer Australia; 2004.)

Mechanism of Action
Like other imidazole and triazole class antifungals, fluconazole inhibits the

fungal cytochrome P450 enzyme 14-demethylase. Mammalian demethylase activity is much less sensitive to fluconazole than fungal demethylase. This inhibition prevents the conversion of lanosterol to ergosterol, an essential component of the fungal cytoplasmic membrane and subsequent accumulation of 14-methyl sterols. Fluconazole is primarily fungistatic; however, it may be fungicidal against certain organisms in a dose-dependent manner, specifically Cryptococcus.

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Manufacture of Fluconazole

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Manufacture of Fluconazole

Chapter 2 History
1969 heralded the discovery of azole antifungal agents. Imidazole agents such as Clotrimazole, miconazole, sulconazole and bifonazole acted by binding to cytochrome p450, thus blocking ergosterol synthesis in the fungal cell membrane. Then came the devolpment of triazole antifungal agents that were less likely to cause heptotoxicity possibly due to their diminutive effects on cytochrome p-450-dependent enzymes. Terconazole was the first triazole developed, followed by itraconazole and finally FLUCONAZOLE.

Development of Fluconazole
In 1978 Pfizer based in Sandwich, Kent started a programme to find an agent to improve on the available medicines culminating in the creation of fluconazole, 2-(2,4difluorophenyl)-1,3-bis (1H-1,2,4-triazol-1-yl)-2-propanol. The characteristic list

required that the agent had to be safe,having wide range of action,effective both orally and intravenously enabling the drug to be used against common infections such as vaginal candidiasis and also used intravenously for seriously ill patients. Attention was turned to th e triazole tertiary alcohol derivatives in which the R substituent was varied, in order to obtain compounds resistant to metabolism and of low lipophilicity. The first group used was a 1,2,4-triazole, which resulted in the formation of the bistriazole UK-47,265. This compound performed outstandingly in a mouse model of candidiasis, being almost 100 times more potent than ketoconazole. Many bis-triazoles were formed by replacing the dicholorophenyl unit. It was found that only the 2,4difluorophenyl analogue of was water soluble, thus allowing formulation for intravenous administration. It was finally named Fluconazole in 1982 after performing excellently in tests on fungal infections in both normal as well as immunosuppressed systems in animals.
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Manufacture of Fluconazole

The data from this as used for registration of the compound with governments for market approval and fluconazole was marketed as Diflucan in the US and UK and over 30 countries worldwide.

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Manufacture of Fluconazole

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Chapter 3 Literature review

Fluconazole is approved by the FDA for the treatment of systemic candida infections.Fluconazole was recommended as primary therapy for candedemia in stable neutropenic patients in whom C.Krusei was unlikely and who had received no prior treatment with Fluconazole. Fluconazole is chosen over Amphotericin B,precisely because of its lesser toxicity.Experts selected Fluconazole as initial therapy for stable patients who did not receive Fluconazole previously for candedemia after Solid organ transplant. Candida Peritonitis,chronic disseminated candidiasis in patients who are no longer neutropenic and uncomplicated candida endophthalmitis were treated with Fluconazole either alone or in combination with Amphotericin B or 5-FC. Fluconazole has been widely used to treat mucocutaneous candidiasis,particularly in HIV infected patients. Oropharyngeal and esophageal candidiasis,a frequent and severe problem in patients with advanced HIV infection,is effectively treated with Fluconazole. Those who failed to respond to standard dose were switched to 800 mg/day oral suspension.

Sheehan et . al.,1999.

Isolated Pulmonary Cryptococcosis (IPC),an infection that occasionaly disseminates and develops disabling symptoms in some patients, is extremely difficult to diagnose and tends to occur most often in immunocompromised hosts. Yamaguchi and colleagues treated 44 patients with Fluconazole of which 22 had IPC,with a dose of 200-400 mg per day. 86% of the patients with IPC were classified as cured or improved. In the study of Dromer et al,Fluconazole was utilised in the therapy of 40 patients,15 of whom did not have meningial involvement. 93% of the patients without meningitis receiving Fluconazole were cured. 4 cases of IPC in immunocompetent hosts treated with

Fluconazole ,but initially treated with Amphotericin B,were described by Yew et al.The

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Manufacture of Fluconazole

dosage of Fluconazole was 600 mg/d orally for 4 to 5 weeks followed by 400 mg/d for 10 to 12 weeks. 100 % of the patients were cured. N ez et . al ., 2000

In "Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized placebo-controlled trial", Marr et al.,(2000),results were reported of long-term follow-up and a detailed analysis of invasive candidiasis and candidiasis-related death in 300 patients who received fluconazole(400 mg/d) or placebo for 75 days after BMT at the Fred Hutchinson Cancer Research Center. Patients in both treatment arms were compared for survival, causes of death, and the incidence of

invasive fungal infections early (less than 110 days) and late (more than 110 days) after BMT.After 8 years of follow-up, survival is significantly better in fluconazole recipients compared with placebo recipients (68 of 152 vs 41 of 148, P 5 .0001). The overall incidence of invasive candidiasis was increased in patients who received placebo compared with fluconazole (30 of 148 vs 4 of 152, P < .001). More patients who received placebo died with candidiasis early (13 of 148 vs 1 of 152, P 5 .001) and late (8 of 96 vs 1 of 121, P 5 .0068) after BMT. The incidence of severe GVHD involving the gut was higher in patients who did not receive fluconazole (20 of 143 vs 8 of 145, P 5 .02), and fewer patients who received fluconazole died with this complication. Thus, administration of fluconazole (400 mg/d) for 75 days after BMT appears to be associated with decreased gut GVHD, a persistent protection against disseminated candidal infections and candidiasis-related death, resulting in an overall survival benefit in allogeneic BMT recipients. Marr et . al., 2000

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Manufacture of Fluconazole

Oropharyngeal candidiasis is the most common fungal infection in patients with HIV infection. Ketoconazole,the first of the azole antifungal agents introduced,was found to be efficacious in the setting of chronic mucocutaneous candidiasis.However, not long after the introduction of this agent,reports of clinical failure in association with elevated MICs of ketoconazole that developed during prolonged therapy began to appear. Subsequently fluconazole was introduced. Its a water soluble triazole extensively used to treat a wide range of Candida infections. However,same problems of high MICs were encountered with Fluconazole.However, Mycological failure (failure of therapy to eradicate the yeast) is hard to interpret because many patients improve clinically despite the persistence of yeasts.The majority of patients with Candida infections, including AIDS patients with oropharyngeal candidiasis, do now and will likely continue in the future to respond at least initially to fluconazole treatment. Rex et. al .,1995

The distribution and fluconazole susceptibilities of Candida species isolated over a 5year period were investigated. Susceptibilities were determined by using a new microtiter procedure and the National Committee for Clinical Laboratory Standards (NCCLS) proposed standard. Results indicated that there is species related difference in MICs.While amphotericin B was the only drug available for therapy in patients with serious fungal infections, susceptibility testing was considered unnecessary (3, 4). With the recent availability of the newer azoles, however, this situation was to change (7).A new method for testing susceptibility of yeast by broth microdilution was introduced.The aim was to study and evaluate fluconazole susceptibility of candida species. Susceptibility testing was carried out from variety of sources like blood,sputum and urine.These consisted of Candida albicans (157 isolates), Candida glabrata (66 isolates), Candida tropicalis (48 isolates), Candida parapsilosis (40 isolates), and Candida krusei (18 isolates) and included a total of 329 strains.It was found that Candida albicans is the most susceptible while Candida glabrata is the least susceptible to Fluconazole. Price et. al .,1999
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Physical and Chemical Properties of reactants and products. A) REACTANTS

1) 2,4-Difluoro-alpha-(1H-1,2,4-triazolyl)acetophenone

CAS No. Chemical Name triazolyl)acetophenone Synonyms :

: :

86404-63-9 2,4-Difluoro-alpha-(1H-1,2,4-

DFTA;4-Difluoro-2(1h-1;4-triazol-1yl)acetophenone;1-(2,4-Difluorophenyl)-2-(1H1;Difluoro triazolyl acetophenone;2,4-Difluoro-3broMo acetophenone;Voriconazole

CBNumber Molecular Formula Formula Weight MOL File mp storage temp. CAS DataBase Reference

: : : : : : :

CB6684361 C10H7F2N3O 223.18 86404-63-9.mol 103-107 C(lit.) Room temperature. 86404-63-9(CAS DataBase Reference)

Chemical Properties Pale Yellow Solid

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Usage Antifungal activity, particularly toward Candida albicans and Candida parapsilosis

2)Trimethylsulfoxonium Iodide
Specifications Product Synonyms CAS NO. Molecular Formula Molecular Weight Appearance Solubility Total Moisture Melting Point Assay on dry basis : : : : : : : : : : : Trimethylsulfoxonium Iodide Trimethylsulfoxonium Iodide Trimethylsulfoxonium Iodide [1774-47-6] C3H9IOS (Trimethylsulfoxonium Iodide) 220.07 White to cream coloured crystals. soluble in hot water. 0.5% max. 168' - 172' C 99% min.

3) 1H -1,2,4-triazole
1,2,4-Triazoles can be prepared using the Einhorn-Brunner reaction or the Pellizzari reaction.[1] The ring structure appears in certain N-heterocyclic carbenes. Identifiers CAS number : 288-88-0

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PubChem ChemSpider ChEBI CHEBI: Properties. Molecular formula Molar mass Appearance Melting point Boiling point Solubility in water Acidity (pKa) Basicity (pKb) Flash point Related compounds

: : :

9257 8900 46077

: : : : : : : : : :

C2H 3N3 69.0654 white solid 120-121 260 very soluble 2.2 10.3 140 1,2,3-triazole imidazole

B) PRODUCTS: 1)Fluconazole
CAS No. Chemical Name: Synonyms : : : 86386-73-4 Fluconazole Elazor, Flusol, Zoltec, uk49858, diflucan, Fluconal, FluMycon,Flunazol,Triflucan.
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CBNumber Molecular Formula Formula Weight MOL File Fluconazole Property mp storage temp. solubility form CAS DataBase Reference Safety Hazard Codes Risk Statements Safety Statements RTECS

: : : :

CB3740293 C13H12F2N6O 306.27 86386-73-4.mol

: : : : :

138-140C 20C DMSO: 5 mg/mL solid 86386-73-4(CAS DataBase Reference)

: : : :

Xn,Xi 22-36/37/38-20/21/22 26-36-36/37/39-24/25 XZ4810000 86386-73-4(Hazardous Substances Data)

Hazardous Substances Data : Chemical Properties White to Off-White Solid Usage:

Labelled Fluconazole (F421000). Used as an antifungal. Biological Activity

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Triazole antifungal agent. Effective against Candida strains in vitro and in vivo . Fluconazole Preparation Products And Raw materials

2) Dimethyl Sulphoxide
CAS No. Chemical Name Synonyms : : : 67-68-5 Dimethyl sulfoxide m176,DMSO,Decap,M 176,Deltan,a10846, Demeso,DMS70,DMS 90, dms-70 CBNumber Molecular Formula Formula Weight MOL File mp bp density vapor density vapor pressure FEMA refractive index Flash point storage temp. : : : : : : : : : : : : CB7854105 C2H6OS 78.13 67-68-5.mol 18.4 C 189 C(lit.) 1.100 g/mL at 20 C 2.7 (vs air) 0.42 mm Hg ( 20 C) 3875 n20/D 1.479(lit.) 192 F Store at RT.
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color FreezingPoint Sensitive Merck BRN CAS DataBase Reference NIST Chemistry Reference EPA Substance Registry System Safety Hazard Codes Risk Statements Safety Statements WGK Germany RTECS HS Code

: : : : : : :

clear colourless 18.4 Hygroscopic 14,3259 506008 67-68-5(CAS DataBase Reference) Dimethyl sulfoxide(67-68-5)

Methane, sulfinylbis-(67-68-5)

: : : : : :

Xi 36/37/38 24/25-37/39-26-36-23 1 PV6210000 29309070 67-68-5(Hazardous Substances Data)

Hazardous Substances Data : Chemical Properties colourless liquid

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General Description A clear liquid, essentially odorless. Closed cup flash point 192F. Vapors are heavier than air. Contact with the skin may cause stinging and burning and lead to an odor of garlic on the breath. An excellent solvent that can transport toxic solutes through the skin. High vapor concentrations may cause headache, dizziness, and sedation. Air & Water Reactions Denser than water and miscible in water. Reactivity Profile Dimethyl sulfoxide decomposes violently on contact with many acyl halides, aryl halides and related compounds such as phenyl and tolyl chloride, acetyl chloride, benzenesulfonyl chloride, benzoyl chloride, cyanuric chloride, phosphorus chloride, phosphorus oxychloride, and thionyl chloride [Chem. Eng. News 35(9):87 (1957)]. Reacts, possibly violently, with iodine pentafluoride [Chem. Eng. News 47(12):, 109(1969)]. Vacuum distillation from anhydrous magnesium perchlorate led to an explosion [MCA Case History 1187(1966)]. Violently reactive with fluorinating agents such as silver fluoride [Chem. Eng. News 44(24):7(1956)]. Can explode with sodium hydride [Chem. Eng. News 44(24):7(1966)]. Mixture with methyl bromide resulted in an explosion that shattered the apparatus [NFPA 491M, 1991]. Forms salts with perchloric acid that are explosive when dry [Chem. Abst. 44:p3935d (1950)]. Decomposes when heated above normal boiling point. Health Hazard Slight eye irritation.

Fire Hazard Special Hazards of Combustion Products: Sulfur dioxide, formaldehyde, and methyl mercaptan can form
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Biological Activity Solvent with wide ranging applications in biological research.

3) Sodium Iodide
CAS No. Chemical Name Synonyms : : : 7681-82-5 Sodium iodide Ioduril,Soiodin,Anayodin,jodidsodny, Jodid sodny sodiumiodine;natriiiodidum; SODIUM IODIDE;Sodium iodine CBNumber Molecular Formula Formula Weight MOL File Sodium iodide Property mp bp density vapor density refractive index Fp storage temp. : : : : : : : 661 C(lit.) 1300 C 3.66 >1 (vs air) 1.7745 1300-1304C Store at RT.
19

: : : :

CB6170714 INa 149.89 7681-82-5.mol

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Manufacture of Fluconazole

form Water Solubility Sensitive Merck CAS DataBase Reference NIST Chemistry Reference EPA Substance Registry System Safety Hazard Codes Risk Statements Safety Statements WGK Germany RTECS F HS Code Hazardous Substances Data

: : : : : : :

beads 184 g/100 mL (25 C) Hygroscopic 14,8631 7681-82-5(CAS DataBase Reference) Sodium iodide(7681-82-5) Sodium iodide (NaI)(7681-82-5)

: : : : : : : :

Xi 36/38-36/37/38 26 1 WB6475000 8 28276000 7681-82-5(Hazardous Substances Data)

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Chapter 4 Methods of manufacture

Several methods for the synthesis of Fluconazole are reported in the literature. Some prominent ones are listed below: 4.1.1 Synthesis of Fluconazole starting from 1,3-Difluorobenzene. It comprises of the following steps:

Fluconazole
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4.2.2 Synthesis of Fluconazole Triazole-1 yl) Acetophenone.

from

2,4-Difluoro-2-(1H-1,2,4-

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The above process (2) ,(i.e. the synthesis of Fluconazole from 2,4-Difluoro-alpha-(1H1,2,4-triazolyl)acetophenone, Tri Methyl Sulphoxinium Iodide and 1H-1,2,4-Triazole) has been selected in Polydrug Laboratories Pvt.Ltd because: The process (1) of manufacturing Fluconazole from 1,3-Difluorobenzene has very low overall yield of only 4-8 % of Fluconazole. The other major process used in manufacture of Fluconazole requires reactant which is produced by reaction of 1,3-ditriazole acetone with the corresponding Grignard of

Difluorobenzene. However, the solvents used in both lithiation and Grignard reactions are extremely flammable and hazardous. The reagents and solvents are dangerous to handle in large quantities,hence this method is not very attractive for large scale commercial production. Thus, in comparison to these methods,the method employed in Polydrug Laboratories Pvt. Ltd. Utilises materials which are readily available commercially,easily

handled,relatively inexpensive and relatively safe to use.

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Material Balance? Energy balance? Thermodynamic feasibility?

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Chapter Energy Balance

One of the most important parameters in a chemical industry is the temperature at which chemical reaction is carried out.Thus depending upon whether the reaction is endothermic or exothermic,heat is either absorbed or evolved.Thus we provide cooling utilities to keep the reaction constant in an exothermic reaction and heating utilities to keep the reaction temperature constant in an endothermic reaction. In our process for manufacture of Fluconazole, heat is liberated by the following reaction. DFTA + TMSI + 1 H-1,2,4 Triazole

Fluconazole

DMSO

NaI

As we know, heat of reaction ( HR) is calculated as follows : HR = (HR)298 + CP dT where CP But (CP) PRODUCTS Thus, HR = (HR)298 We use Joback group contribution theory to calculate the Standard Heat of Formation of each reaction species and product species and then we proceed to calculate the overall Heat of Reaction . = = (CP) PRODUCTS - (CP) REACTANTS (CP) REACTANTS

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A) 2,4-Difluoro-2-(1H-1,2,4-Triazole-1 yl) Acetophenone.

Functional Group =N- (ring) F=CH- (ring) =C= (ring) =C= (non ring) O= (non ring) =CH2 (non ring)

No of groups 3 2 5 3 1 1 1

(Hj)298 55.52 -251.9 2.09 46.43 83.99 -247.6 -20.64

Hj 166.56 -503.8 10.45 139.29 83.99 -247.6 -20.64

Hence, H (DFTA)

= =

, Hj + 68.29 -293.46 kcal/mol

B) Trimethyl Sulphoxinium Iodide

Functional Group -CH3 (non ring) IO= (any other) <=S=> No of groups 3 1 1 1 (Hj)298 -76.45 21.06 -247.6 41.87 Hj -229.35 21.06 -247.6 41.87

Hence, H (TMSI)

= =

Hj + 68.29 -345.73 kcal/mol

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C) 1H-1,2,4-Triazole

Functional Group -N= (ring) =NH (ring) -CH= (ring)

No of groups 2 1 2

(Hj) 298 55.52 31.65 2.09

Hj 111.04 31.65 4.18

Hence,

H (1H-1,2,4-Triazole)

Hj + 68.29

215.16 kcal/mol.

D) Fluconazole
Funtional Group F=N- (ring) =C= (non ring) OH=CH2 (non ring) =CH- (ring) =C= (ring) No of groups 2 6 1 1 2 7 3 Hj298 -251.9 55.52 82.23 -208 -20.64 2.09 46.43 Hj -503.8 333.12 82.33 -208 -41.28 14.63 139.29

Hence, H (Fluconazole)

= =

Hj + 68.29 -115.52 kcal/mol

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E)

Dimethyl Sulphoxide
No of groups 2 1 1 Hj298 -76.45 41.87 -247.6 Hj -152.9 41.87 -247.6

Functional Group -CH3 -SO=

Hence, H(DMSO)

= =

Hj + 68.29 -290.34 kcal/mol.

F) Sodium Iodide
H ( NaI) = -68.784 kcal/mol.

Thus, HR

= =

H PRODUCTS

HREACTANT

[HFLUCONAZOLE+HDMSO+HNAI] [ HDFTA+HTMSI+HTRIAZOLE]

= =

-474.644 - [-424.03] -50.614 Kcal/ kmol.

Thus, Reaction is exothermic. We provide cooling utility i.e. cooling water to keep temperature constant. Heat evolved by chemical reaction H Where, Tin = = = = Heat gained by cooling water m * Cp * ( T in T out) .. ( 1 ) 5 C. 278 K

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Cp Lets H

4.187 KJ/ Kg K. 303 K (Kmole of DFTA reacted) * (HR in KJ/Kmol) 0.966 * ( - 50.614 * 4.187) -204.71 * 10 ^ 3 KJ

Tout = = = =

Thus, from above equation ( 1 ), value of mass of water required per batch can be obtained. Thus, m m = = 1955.67 1.956 kg per batch

tons per batch

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Chapter Equipment Design

Density of DFTA Density of H20 Density of 1 H-1,2,4-Triazole Density of NaOH Density of TMSI

= = = = =

1390 kg/m3 1000 kg/m3 1394 kg/m3 2130 kg/m3 1390 kg/m3

Volume of DFTA

= =

400/1390 0.288 m3 160/2130 0.075 m3 6000/1000 6 m3 400/1399 0.286 m3 160/1394 0.115 m3

Volume of NaOH

= =

Volume of H2O

= =

Volume of TMSI

= =

Volume of 1 H-1,2,4-Triazole

= =

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Total Volume = Vol ( DFTA ) + Vol ( NaOH) + Vol ( H2O) + Vol (TMSI) + Vol ( 1 H-1,2,4-Triazole)

Total Volume

6.764 m3

This is the Hold up volume. Holdup volume is generally 75 % of the Total volume. Hence , Total Volume Concentration in Feed =
= = Thus, C ( DFTA) = = C ( TMSI) = = C ( NaOH) = = C ( 1 H-1,2,4-Triazole) = = 400/ ( 223 * 6.764 ) 0.265 kmol/m3 400/( 220 * 6.764 ) 0.2688 kmol/ m3 160/ ( 40 * 6.764) 0.591 kmol/m3 160/ ( 69 * 6.764) 0.343 kmol/m3

9.019 m3
Moles / Volume Mass / ( Molecular weight * Volume)

Also, Total Volume

Generally, D= 0.8 H Thus, Thus, 9.019 H D

( / 4) * D2 H

= = =

(/4) * (0.8 H) * H 2.618 m 2.094 m.

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Chapter Mechanical Design

Design Pressure

= =

3 kg/ cm2 0.3 N/ mm2

A) Thickness of Shell :
ts = = = Take ts = ( P * di ) / ( 2 f J P ) + c ( 0.3 * 2094) / ( 2 * 110 * 0.85 - 0.3) + 2 5.36 mm. 6 mm

Now, lets check if the resultant stress allows for thickness obtained from above calculation. Calculation for the resultant/ equivalent stress for cylindrical vessel under combined loadings. 1) Circumferential stress ft ft = = = P ( Di + t) / ( 2 t) ( 0.3 * (2094 + 6) ) / ( 2 * 6 ) 52.5 N/ mm2

2) Stresses in axial direction.

a) Due to internal pressure:

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fL1 = P ( Di + t) / ( 4 t ) fL1 = 26.25 N/ mm2

b) Due to weight of the vessel and its contents for vertical vessel. W/ ( * ( Di + t) t )

fL2

Here, W is the total weight of the vessel alongwith its contents, fittings,auxialliary equipments , etc. It is expressed in Newtons. Also W is obtained by increasing the weight of the vessel and its contents by 10 to 15 % , to take care of the weight due to various fittings and auxiliary equipments.

Let Wo be the weight of the vessel. Wo = = = Thus, W = density * volume * 9.81 8000 * 9.019 * 9.81 707811.12 N Wo + 0.15 W

813982.79 N ( 813982.79) / ( * (2094 + 6 ) * 6 ) 20.56 N/ mm2

fL2

fL2

c)

Due to wind load. fL3 = 0 ( No wind Load )

Thus resultant stress in the longitudinal direction : fLR =

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= fLR 3) Torsional stress =

26.25 + 20.56 46.81 N/mm2

Torque on vessel

= =

37 kN m 37 * 10 ^ 6 N mm 2 T / ( * Di * t * (Di + t)) ( 2 * 37 * 10 ^ 6 ) / ( * 2094 * 6* 2100)

Stress due to torque

( fs )

= =

fS

= 0.893 N / mm2

Resultant stress i.e. fR

fR

= ( fT 2 f T * f LR + fLR 2 + 3 fs 2 )

= ( 52.52 52.5 * 46.81 + 46.82 + 3* 0.8932) = 58.69 N / mm2

Hence , fR

As this resultant stress is less than the permissible stress of 110 N/mm2 that we utilized earlier, the thickness obtained is satisfactory and design is safe. Thus, including corrosion allowance of 2 mm , take shell thickness ts = 8 mm.

Outer diameter of shell

= =

inner diameter + 2 tS 2094 + 16

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2110 mm.

Design Procedure is applicable to shell having ratio of (Do/ Di) < 1.5 Here, (Do/ Di) = = Hence, (Do/ Di) < 2110/ 2094 1.008 1.5

Hence, procedure holds for good design.

B) Design for Head

For flanged and shallow dished head : Th Where, Rc = = = W W But, Rk Rk = = = = = W W J = = = ( P Rc W ) / ( 2 f J) Crown radius 2094 mm stress intensification factor (1/4) * ( 3 + ( Rc / Rk ) ) 6 % of Rc 0.06 * 2094 125.64 mm. (1/4) * ( 3 + ( 2094 / 125.64 )) 1.77 1 ( for head )
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Thus , we have

Th Th

= =

( 0.3 * 125.64 * 1.77 ) / ( 2 * 110 * 1) 0.303 mm.

Including corrosion allowance of 2 mm, Th = 3 mm.

We take Th as 8 mm as its thickness of shell.

C) Jacket Design

We use conventional or Plain jacket. a) Jacket shell thickness for internal pressure. Dij = = t rj Design Pressure = = = trj trj Including corrosion allowance take trj = 10 mm. Dso + 1.2 2230 mm. ( Pj Dij ) / ( 2 f J Pj) 6 0.6 kg/ cm2 N/ mm2

= ( 0.6 * 2230 ) / ( 2 * 110 * 0.85 0.6 ) = 7.178 mm

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b) Jacket Closer Thickness It should be the higher value of the following : i) trc trc ii) trc = = = = = 2 * t rj 2 * 10 20 mm 0.866 * Wj ( Pj / f ) Jacket width

Here, Wj But, Jacket width =

( Inside dia. Of Jacket Outside dia. Of vessel) / 2 Wj Wj = = = = = (2230 2110 ) / 2 60 mm. 0.866 * 60 * ( 0.6 / 110 ) 3.84 mm 20 mm.

Thus, trc trc Hence, take higher value of trc , i.e. trc

Design of jacket torispherical end for internal jacket pressure

Thickness of jacket head: thj = = thj = (P Rc W) / ( 2 f J ) ( 0.6 * 2230 * 1.77 ) / (2 * 110 * 1) 1.076 mm.

Thus, we use 5 mm thickness for jacket torispherical end.

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D) Design of Flange And Bolts

I)

Design of gasket. Do Gi Gi Gi = = = = = = = = Thus , Go Go = = 2110 mm. Do + 10 Do + 10 2120 mm. ( ( y pm) / ( y p (m+1))) outer diameter of gasket. gasket seating stress. 11 N/ mm2 Gi * ( ( y pm) / ( y p (m+1))) 2151.25 mm. ( Go Gi ) / 2 ( 2151.25 2120) / 2 15.63 mm N/2 15.63 / 2 7.814 mm.

Outer diameter of shell Thus, Inner diameter of gasket Thus, Inner Diameter of gasket

Also,

( Go/ Gi) Where, Go Y

Thus, width of the gasket

(N) = N N = = = = bo =

Basic Gasket Seating width ( bo)

Now,

as bo > 6.3 mm , efeective gasket seating width ( b) is given as : b b = =

41

2.5 * (7.814) 6.988 7 mm.

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Diameter of gasket at load reaction ( G )

= =

Go 2 b 2151.25 - 2 ( 7 ) 2137.25 mm.

G II) Design of Bolt :

Bolt load under atmospheric condition : Wm1 = = Wm1 Bolt load under operating conditions : Wm2 Wm2 As Wm2 > Wm1, we take this value. Hence, area of bolt required is Ab Ab But, Ab Where, n n n Take Thus db n db = = = Wm / ( fb ) = ( 1132672.07 / 53) 21371.17 mm2 n * ( /4 ) * db 2 = = G * 2b * m * p + ( /4) G2 * P 1132672.07 N = Gby * 2137.25 * 7 * 11 517006.41 N

= no. of bolts. = = = = = G/ 25 = 86 88 ( multiple of 4 ) ( (4 * ) / ( A/ n )) 17.58 18 mm. 2137.25/ 25

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Use M18 * 2 bolts, 88 numbers. Bolt circle diameter (B) B B Thus, B Actual bolt spacing required bs = = = = = = bs III) Design of Flange = = Dfo = B + 2 db+ 12 2200 + 2 ( 18) + 12 2248 mm. = Go + 2 db +12 2151.25 + 2 (18) + 12 2199.25 mm 2200 mm. B/ n ( * 2200 ) / 88 78.54 mm

Outside diameter of the flange Dfo

1 / ( 0.3 + 1.5 Wm hG / (HG) )

where,

Wm

= =

Max bolt load 1132672.07 N (B - G) / 2 ( 2200 2137.25) / 2 31.38 mm. (/4) * G 2 P

hG

= =

hG H

= =

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H Thus, Thickness of flange k tf tf Thus,

= = = = tf =

1076271.37 3.0943 G ( P/ k f) 2137.25 ( 0.3 / ( 3.0943 * 110 )) 63.45 mm 65 mm.

E) Nozzle Reinforcement Design

Design Pressure Diameter of nozzle = = 0.3 N / mm2 100 mm.

Material of nozzle is same as that of reactor. Thickness of nozzle ( tn) tn tn = = = Horizontal diameter for compensation AB = = = Vertical Diameter for Compensation. We take the greater value of the following: i) AD =
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P Di / ( 2f J P) ( 0.3 * 100 ) / ( 2 * 110 * 1- 0.3) 0.1365 mm. 1 mm.

2 Dn 2 * 100 200 mm

6 * tn

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= ii) AD = = AD Take greater value , i.e. Area of Compensation AD = = = = Area of compensation provided by head Ah = = = Area of compensation provided by nozzle Where, Ht = = = tn tn Thus, Ao Ao = = = =

6 * 3 = 18 mm. 3.5 * ts + 2.5 tn 3.5 * 8 + 2.5 * 3 35.5 35.5 100 * 8 800 mm2 Din* ( ts ts ) 100 * (8-6) 200 mm2

2 Ht * ( tn tn c) 2.5 * ts 2.5 * 8 = 20 mm. 3 0.1365 2 * 20 * ( 3- 0.1365 0 ) 114.54 mm2

Nozzle does not project inside the vessel. Thus, H2 and At =0. Total area of compensation available = = = An + Ao + At 200 + 114.54 + 0 314.54 mm2

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Hence, as the area of compensation required is 300 mm2 and 314.54 mm2 is already available, no ring is required.

Design For Agitator

Power required for agitator (P)

(Np * * N ^3 * Da^5) / (gc * 75)

Where ,

= =

10 rpm 0.1667 rps 9.81 m/ sec2 1.01 m

gc Agitator Diameter (Da)

= =

To find density of reaction mixture ( )

Density of fluid entering the reactor Where, Mass Volume = = = Mass / Volume Mass ( Reactants + Water) Volume (Reaction Mixture )

Total mass of reactants

( 400 kg DFTA + 400 kg TMSI + 160 kg 1 H-1,2,4-Triazole + 160 kg NaOH )

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Total mass of reactants Mass of Water Thus, total mass

= = =

1120 kg. 6000 kg 7120 kg.

Volume of water fed

= =

6000/ 1000 6 m3 Mass/ Volume 400/1390 0.288 m3

Volume of DFTA fed

= =

Volume of DFTA fed Similarly, Volume of NaOH fed

= =

160/2130 0.075 m3 400/ 1399 0.286 m3 160/ 1394 0.115 m3 Volume ( water + reactants ) 6 + ( 0.764) 7120 kg/ 6.764 m3 1052.63 kg/m3

Volume of TMSI

= =

Volume of 1 H-1,2,4-Triazole

= =

Thus, Total Volume of Reaction Mixture

= =

Hence, density of reaction mixture ()

= =

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To find Power number

Power number ( Np) can be approximated from a graph of log ( Np) v/s log ( NRe) NRe is Reynolds number. But, Let Nre N = = ( N Da^5 ) / 10 rpm for highly viscous fluid.

The value of of reaction mixture is taken as the viscosity of Fluconazole suspension in water as gel. Thus , Hence , Nre Nre From log Np v/s log Nre graph, Np = = = = 103.96 pascal sec. 1052.63 * 0.1667 * ( 1.01 )^5 / 103.96 2 28

Hence , Power required for agitator ( P) P

= =

(Np * * N ^3 * Da^5) / ( gc * 75 ) 0.196 hp

Considering 10 % gland losses and 20 % transmission losses ,power required is 0.259 hp. Select 0.5 hp motor.

1) Shaft design
Rated Motor torque ( Tr) = = Tr Maximum Torque (Tm) = = =
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( P * 4500) * 10 ^4 / ( 2 N ) N mm. (0.5 * 4500) * 10 ^4 / ( 2 * 10) 358098.62 N mm 1.5 Tr 537147.93 N mm.

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a) But, Where, Thus, 537147.93

Tm fs

= = =

( / 16 ) * fs * d ^3 125 N/ mm2 for SS 316. (/16) * 125 * d ^3 27.97 mm.

b) This Tm is resisted by the Fm which acts at 75 % of max radius of impeller. Thus, Where, Fm Rb = = = Fm But, Mm = = Tm / ( 0.75 * Rb) radius of blade in mm. 505 mm 1418.21 N Fm * L

Where L is shaft length between agitator and bearing. Mm Mm Also, Where, Mm fb fb Hence, 1276389 d = = = = = = = 1418.21 * 900 1276389 N mm ( / 32) * fb * d^3 bending stress 230 N/ mm2 for S.S. ( / 32) * 230 * d ^ 3 38.38 mm.

Also, by maximum shear stress theory, Equivalent twisting moment ( Te) is given as : Te = ( Mm2 + Tm2 )

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Te Te But, =

( 1276389 ^ 2 + 537147.93 ^ 2)

1.38 * 10 ^ 6 N/ mm2 Te d = = ( / 16) * fs * d^3 38.31 mm.

Also, by maximum normal stress theory , Equivalent Bending moment ( Me) : Me Me Also, 1.33 * 10 ^ 6 d Me = = = = = (1/2) * ( Mm + ( Mm ^ 2 + Tm ^ 2)) 1.33 * 10 ^ 6 N/ mm2 ( / 32) * fb * d ^3 ( / 32) * 230 * d ^ 3 38.91 mm.

Thus, we obtained 4 values of shaft diameter ( d) . We select the highest value , i.e. d = 38.91 mm Or d 40 mm.

Hence, actual value of shaft diameter = 70 2 mm is adequate.

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Design of Centrifuge
Top discharge with hydraulic power pack arrangement for lifting bag and lid.

Basket Diameter Thickness of basket Overall Height of basket

= = =

1210 5 mm 6 1 mm. 1650 mm.

The overall dimensions of the basket are as follows: 1210 mm Diameter * 500 mm Height * 6 mm Thickness

Now, let us find out if this thickness provided is adequately safe for operation at a particular rpm. Let = = 750 rpm 78.54 rad / sec

Let the solid cake obtained have a thickness of 100 mm. Pressure exerted ( Pc) by the solids on the wall of the basket is given by: Pc Where, b a = = = = = 0.5 * * ^2 * ( b2 a 2) density of solids. angular velocity. radius of basket. radius of inner surface of solids

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= =

radius of basket thickness of solid layer 0.605 - 0.1 0.505 m 78.54 rad / sec

= =

To find density of solids ( ) : i) Density of each species = = = = = = = 1490 kg/ m3 1399 kg/ m3 2130 kg/m3 1390 kg/m3 1394 kg/m3 1100 kg/m3 3670 kg/m3

Density of Fluconazole Density of TMSI Density of NaOH Density of DFTA Density of 1H-1,2,4-Triazole Density of DMSO Density of NaI

ii)

No. of moles of each species in centrifuge: = = = = = = 0.947 0.947 0.947 0.827 0.844 1.344

Kmol of Fluconazole Kmol of NaI Kmol of DMSO Kmol of DFTA Kmol of TMSI Kmol of 1H-1,2,4- Triazole

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iii)

Mass of each species in centrifuge = kmol * molecular weight. = = 0.947 * 306 289.78 kg. 0.947 * 150 142.05 kg. 0.947 * 78 73.87 kg. 0.827 * 223 184.421 kg. 0.844 * 220 185.68 kg. 69 * 1.344 92.72 kg. 122.12 kg.

mass of Fluconazole

mass of NaI

= =

mass of DMSO

= =

mass of DFTA

= =

mass of TMSI

= =

mass of 1 H 1,2,4-Triazole

= =

mass of NaOH

iv)

Mass fraction of each species = = = = = 0.265 0.13 0.067 0.169 0.17

Fluconazole NaI DMSO DFTA TMSI

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1 H-1.2.4-Triazole NaOH

= =

0.088 0.111

Hence, density of solids = average density of solids in the product mixture in centrifuge. i.e. thus, = = i xi 1773.31 kg/m3

Hence, 0.505 ^2)

Pc

0.5 * 1773.31 * ( 78.54) ^ 2 * (0.6^2 -

Pc

5.74 * 10^ 5 N / mm2.

Also, stress ( f) in the basket walls is given as: f But, f = = ( b/ ) * ( Pc + m * * b * ^ 2) 110 N/ mm2 for SS 316

Above equation has only one unknown i.e. . Thus by substituting the values of the other variables in the above equation, we have 110 * 10 ^6 = (0.605/ ) * ( 5.74 * 10 ^ 5 + ( 2.99 * 10^7))

Thus,

3.78 mm

The minimum thickness of centrifuge required to have safe design is 3.78 mm. But , the actual thickness is 6 mm.

Hence, our design is safe.

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Fluconazole MSDS
Section 1 Chemical Product and Company Identification Product Name Catalog Codes CAS# RTECS TSCA CI# Synonym Chemical Name : : : : : : : : Fluconazole SLF1666 86366-73-4 XZ4810000 TSCA 8(b) inventory: No products were found. Not available. Fluconazole; Diflucan 2,4-Dfluoro-alpha, alpha-1-bis(1H-1,2,4triazol-1-ylmethyl)benzyl A 1H-1,2,4-Triazole-1-ethanol,alpha(2,4-difluorophenyl)-alpha-(1H-1,2,4triazol-1-ylmethyl)- l c o h o l o r Chemical Formula Contact Information : : C13-H12-F2-N6-O Sciencelab.com, Inc.14025 Smith Rd. Houston, Texas 77396 US Sales: 1-800-901-7247

International Sales: 1-281-441-4400

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Section 2 Composition and Information on Ingredients Name Fluconazole CAS # 86366-73-4 % by Weight 100

Toxicological Data on Ingredients: Fluconazole: ORAL (LD50): Acute: 1271 mg/kg [Rat]. 1408 mg/kg [Mouse].

Section 3 Hazards Identification Potential Acute Health Effects : Slightly hazardous in case of skin Contact (irritant), of eye contact (irritant), of ingestion, of inhalation. CARCINOGENIC EFFECTS MUTAGENIC EFFECTS TERATOGENIC EFFECTS DEVELOPMENTAL TOXICITY : : : : Not available.

Not available. Classified.POSSIBLE for human. Not available. Repeated or prolonged exposure is not known to aggravate medical condition.

Section 4 First Aid Measures

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Eye Contact: Check for and remove any contact lenses. In case of contact , immediately flush eyes with plenty of water for atleast 15 minutes. Get medical attention if irritation occurs.

Skin Contact: Wash with soap and water. Cover the irritated skin with an emollient. Get medical attention if irritation develops.

Serious Skin Contact: Not available.

Inhalation: If inhaled, remove to fresh air. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical attention.

Serious Inhalation: Not available.

Ingestion: Do NOT induce vomiting unless directed to do so by medical personnel. Never give anything by mouth to an unconscious person. If large quantities of this material are swallowed, call a physician immediately. Loosen tight clothing such as a collar, tie, belt or waistband. Serious Ingestion Section 5: : Not available.

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Fire and Explosion Data Flammability of the Product Auto-Ignition Temperature Flash Points Flammable Limits Products of Combustion : : : : : May be combustible at high temperature. Not available. Not available Not available. These products are carbon oxides (CO, CO2) Nitrogen oxides ( NO,NO2), halogenated compounds. Fire Hazards in Presence of Various Substances : Slightly flammable to flammable in presence of heat. Non flammable in presence of shocks. Explosion Hazards in Presence of Various Substances : Risks of explosion of product in presence of mechanical impact : not available. Risks of explosions of the product in Presence of static discharge : not available. Fire fighting Media and instructions : SMALL FIRE: Use DRY chemical powder. LARGE FIRE: Use water spray, fog or foam. Do not use water jet. Special Remarks on Fire Hazards : Not available.

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Special Remarks on Explosion Hazards

Not available.

Section 6: Accidental Release Measures Small Spill: Use appropriate tools to put the spilled solid in a convenient waste disposal container. Finish cleaning by spreading water on the contaminated surface and dispose of according to local and regional authority requirements. Large Spill: Use a shovel to put the material into a convenient waste disposal container. Finish cleaning by spreading water on the contaminated surface and allow to evacuate through the sanitary system.

Section 7: Handling and Storage Precautions: Keep locked up.. Keep away from heat. Keep away from sources of ignition. Empty containers pose a fire risk, evaporate the residue under a fume hood. Ground all equipment containing material. Do not ingest. Do not breathe dust. Wear suitable protective clothing. If ingested, seek medical advice immediately and show the container or the label.

Storage:

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Keep container tightly closed. Keep container in a cool, well-ventilated area. Do not store above 25C (77F).

Section 8: Exposure Controls/Personal Protection Engineering Controls: Use process enclosures, local exhaust ventilation, or other engineering controls to keep airborne levels below recommended exposure limits. If user operations generate dust, fume or mist, use ventilation to keep exposure to airborne contaminants below the exposure limit.

Personal Protection: Safety glasses. Lab coat. Dust respirator. Be sure to use an approved/certified respirator or equivalent. Gloves.

Personal Protection in Case of a Large Spill: Splash goggles. Full suit. Dust respirator. Boots. Gloves. A self contained breathing apparatus should be used to avoid inhalation of the product. Suggested protective clothing might not be sufficient; consult a specialist BEFORE handling this product.

Exposure Limits: Not available. Section 9:

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Physical and Chemical Properties Physical state and appearance Odor Taste Molecular Weight Color pH (1% soln/water) Boiling Point Melting Point Critical Temperature Specific Gravity Vapor Pressure Vapor Density Volatility Odor Threshold Water/Oil Dist. Coeff. Ionicity (in Water) Dispersion Properties Solubility : : : : : : : : : : : : : : : : : : Solid. (Crystalline solid.) Not available. Not available. 306.3 g/mole White. Not available. Not available. Not available. Not available. Not available. Not applicable. Not available. Not available. Not available. Not available. Not available. Not available.

Not available

Section 10:
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Stability and Reactivity Data Stability Instability Temperature Conditions of Instability Incompatibility with various Substances Corrosivity Special Remarks on Reactivity Special Remarks on Corrosivity Polymerization : : : : : Not available. Not available. Not available. Not available. Will not occur. : : : The product is stable. Not available. Excess heat.

Section 11: Toxicological Information Routes of Entry Toxicity to Animals : : Inhalation. Ingestion. Acute oral toxicity (LD50): 1271 mg/kg [Rat]. TERATOGENIC EFFECTS Other Toxic Effects on Humans : : Classified POSSIBLE for human. Slightly hazardous in case of skin contact (irritant), of ingestion, of inhalation.

Special Remarks on Toxicity to Animals :

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Not available.

Special Remarks on Chronic Effects on Humans: May cause birth defects (teratogenic). There are no adequate and well controlled studies of pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers wre being treated for 3 or more months with high doses (400-800 mg/day). Excreted in maternal milk in human.

Special Remarks on other Toxic Effects on Humans: Acute Potential Health Effects: Skin: Eyes: May cause eye irritation. Inhalation: May cause respiratory tract irritation. Ingestion: May cause gastrointestinal tract irritation with nausea, vomiting, abdominal pain, diarrhea, dyspepsia, and tast perversion. May also affect behavior/central nervous system (headache, dizziness, seizures), metabolism (Hypercholesterolemia, Hypertriglyceridemia, Hypekalemia), liver, blood (leukopenia, neutropenia, agranulocytosis, thrombocytopenia), and cardiovascular system. Other symptoms may include skin rashes, exfoliative skin disorders such as Stevens-Johnson syndrome and toxic epidermal necrolysis and alopecia. Anaphylaxis in rare cases has been reported. Clincally or potentially significant drug interactioins between Fluconazole and the follwoing agents/classes have been observed: Oral hypoglycemics, Coumarintype anticoagulants, Phenytoin, Cyclosporine, Rifampin, Teheophylline, Terfenadine, Cisapride, Astemizole, Rifabutin, Tacrolimus.

Section 12: Ecological Information Ecotoxicity : Not available.

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BOD5 and COD Products of Biodegradation

: :

Not available. Possibly hazardous short term degradation products are not likely. However, long term degradation products may arise.

Toxicity of the Products of Biodegradation : The products of degradation are as toxic as the product itself.. Special Remarks on the Products of Biodegradation : Not available.

Section 13: Disposal Considerations Waste Disposal: Waste must be disposed of in accordance with federal, state and local environmental control regulations.

Section 14: Transport Information DOT Classification : Not a DOT controlled material (United

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States) Identification Special Provisions for Transport : : Not applicable. Not applicable

Section 15: Other Regulatory Information Federal and State Regulations : TSCA 8(b) inventory: No products were found. Other Regulations Other Classifications : : Not available. WHMIS (Canada): Not controlled under WHMIS (Canada).

DSCL (EEC)

R22- Harmful if swallowed. R63-Possible risk of harm to the unborn child.

S2- Keep out of the reach of children. S46If swallowed, seek medical advice

immediately and show this container or label. HMIS (U.S.A.) Health Hazard Fire Hazard : : 1 1
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Reactivity Personal Protection

: :

0 E

National Fire Protection Association (U.S.A.) Health Flammability Reactivity : : : 1 1 0

Specific hazard: Protective Equipment: Gloves. Lab coat. Dust respirator. Be sure to use an approved/certified respirator or equivalent. Safety glasses. Section 16: Other Information References Other Special Considerations Created Last Updated : : : : Not available. Not available. 10/09/2005 05:33 PM 06/09/2012 12:00 PM

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Uses
Fluconazole has a variety of applications, especially in severely immunocompromised patients. This includes: For treatment of systemic Candida infections. For Treatment of Oropharangeal and esophageal Candidiasis in patients with advance HIV infection. For treatment of Isolated Pulmonary Cryptococcosis. As a prophylactic drug in patients having undergone bone marrow transplants. For treatment of Hematogenous Candidiasis in Cancer patients. As an antifungal remedy formulation for external application.

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