Final Project Black Book
January 31, 2017 | Author: Shyam Yadav | Category: N/A
Short Description
Download Final Project Black Book...
Description
SSJCOE
Manufacture of Fluconazole
1
SSJCOE
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. It‟s 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)
2
SSJCOE
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
of
fungal
candidiasis,oropharangeal
and
esophageal
ailments
like
mucocutaneous
candidiasis,isolated
pulmonary
cryptococcosis,etc.
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 14α-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 14α-methyl sterols. Fluconazole is primarily fungistatic; however, it may be fungicidal against certain organisms in a dose-dependent manner, specifically Cryptococcus.
3
SSJCOE
Manufacture of Fluconazole
4
SSJCOE
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. 5
SSJCOE
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.
6
SSJCOE
Manufacture of Fluconazole
7
SSJCOE
Manufacture of Fluconazole
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
8
SSJCOE
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
9
SSJCOE
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 10
SSJCOE
Manufacture of Fluconazole
11
SSJCOE
Manufacture of Fluconazole
Physical and Chemical Properties of reactants and products. A) REACTANTS
1) 2,4-Difluoro-alpha-(1H-1,2,4-triazolyl)acetophenone
CAS No.
:
86404-63-9
Chemical Name
:
2,4-Difluoro-alpha-(1H-1,2,4-
triazolyl)acetophenone Synonyms
:
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
:
CB6684361
Molecular Formula
:
C10H7F2N3O
Formula Weight
:
223.18
MOL File
:
86404-63-9.mol
mp
:
103-107 °C(lit.)
storage temp.
:
Room temperature.
CAS DataBase Reference
:
86404-63-9(CAS DataBase Reference)
Chemical Properties Pale Yellow Solid 12
SSJCOE
Manufacture of Fluconazole
Usage Antifungal activity, particularly toward Candida albicans and Candida parapsilosis
2)Trimethylsulfoxonium Iodide Specifications
:
Trimethylsulfoxonium Iodide
Product
:
Trimethylsulfoxonium Iodide
Synonyms
:
Trimethylsulfoxonium Iodide
CAS NO.
:
[1774-47-6]
Molecular Formula
:
C3H9IOS (Trimethylsulfoxonium Iodide)
Molecular Weight
:
220.07
Appearance
:
White to cream coloured crystals.
Solubility
:
soluble in hot water.
Total Moisture
:
0.5% max.
Melting Point
:
168' - 172' C
Assay on dry basis
:
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
13
SSJCOE
Manufacture of Fluconazole
PubChem
:
9257
ChemSpider
:
8900
ChEBI CHEBI:
:
46077
Molecular formula
:
C2H 3N3
Molar mass
:
69.0654
Appearance
:
white solid
Melting point
:
120-121
Boiling point
:
260
Solubility in water
:
very soluble
Acidity (pKa)
:
2.2
Basicity (pKb)
:
10.3
Flash point
:
140
Related compounds
:
1,2,3-triazole imidazole
Properties.
B) PRODUCTS: 1)Fluconazole CAS No.
:
86386-73-4
Chemical Name:
:
Fluconazole
Synonyms
:
Elazor, Flusol, Zoltec, uk49858, diflucan, Fluconal, FluMycon,Flunazol,Triflucan. 14
SSJCOE
Manufacture of Fluconazole
CBNumber
:
CB3740293
Molecular Formula
:
C13H12F2N6O
Formula Weight
:
306.27
MOL File
:
86386-73-4.mol
mp
:
138-140°C
storage temp.
:
−20°C
solubility
:
DMSO: 5 mg/mL
form
:
solid
CAS DataBase Reference
:
86386-73-4(CAS DataBase Reference)
Hazard Codes
:
Xn,Xi
Risk Statements
:
22-36/37/38-20/21/22
Safety Statements
:
26-36-36/37/39-24/25
RTECS
:
XZ4810000
Fluconazole Property
Safety
Hazardous Substances Data :
86386-73-4(Hazardous Substances Data)
Chemical Properties White to Off-White Solid Usage: Labelled Fluconazole (F421000). Used as an antifungal. Biological Activity
15
SSJCOE
Manufacture of Fluconazole
Triazole antifungal agent. Effective against Candida strains in vitro and in vivo . Fluconazole Preparation Products And Raw materials
2) Dimethyl Sulphoxide CAS No.
:
67-68-5
Chemical Name
:
Dimethyl sulfoxide
Synonyms
:
m176,DMSO,Decap,M 176,Deltan,a10846, Demeso,DMS70,DMS 90, dms-70
CBNumber
CB7854105
Molecular Formula
:
C2H6OS
Formula Weight
:
78.13
MOL File
:
67-68-5.mol
mp
:
18.4 °C
bp
:
189 °C(lit.)
density
:
1.100 g/mL at 20 °C
vapor density
:
2.7 (vs air)
vapor pressure
:
0.42 mm Hg ( 20 °C)
FEMA
:
3875
refractive index
:
n20/D 1.479(lit.)
Flash point
:
192 °F
storage temp.
:
Store at RT. 16
SSJCOE
Manufacture of Fluconazole
color
:
clear colourless
FreezingPoint
:
18.4℃
Sensitive
:
Hygroscopic
Merck
:
14,3259
BRN
:
506008
CAS DataBase Reference
:
67-68-5(CAS DataBase Reference)
NIST Chemistry Reference
:
Dimethyl sulfoxide(67-68-5)
:
Methane, sulfinylbis-(67-68-5)
EPA Substance Registry System Safety Hazard Codes
:
Risk Statements
:
36/37/38
Safety Statements
:
24/25-37/39-26-36-23
WGK Germany
:
1
RTECS
:
PV6210000
HS Code
:
29309070
Hazardous Substances Data :
`
Xi
67-68-5(Hazardous Substances Data)
Chemical Properties colourless liquid
17
SSJCOE
Manufacture of Fluconazole
General Description A clear liquid, essentially odorless. Closed cup flash point 192°F. 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 18
SSJCOE
Manufacture of Fluconazole
Biological Activity Solvent with wide ranging applications in biological research.
3) Sodium Iodide CAS No.
:
7681-82-5
Chemical Name
:
Sodium iodide
Synonyms
:
Ioduril,Soiodin,Anayodin,jodidsodny, Jodid sodny sodiumiodine;natriiiodidum; SODIUM IODIDE;Sodium iodine
CBNumber
:
CB6170714
Molecular Formula
:
INa
Formula Weight
:
149.89
MOL File
:
7681-82-5.mol
mp
:
661 °C(lit.)
bp
:
1300 °C
density
:
3.66
vapor density
:
>1 (vs air)
refractive index
:
1.7745
Fp
:
1300-1304°C
storage temp.
:
Store at RT.
Sodium iodide Property
19
SSJCOE
Manufacture of Fluconazole
form
:
beads
Water Solubility
:
184 g/100 mL (25 ºC)
Sensitive
:
Hygroscopic
Merck
:
14,8631
CAS DataBase Reference
:
7681-82-5(CAS DataBase Reference)
NIST Chemistry Reference
:
Sodium iodide(7681-82-5)
EPA Substance Registry System
:
Sodium iodide (NaI)(7681-82-5)
Hazard Codes
:
Xi
Risk Statements
:
36/38-36/37/38
Safety Statements
:
26
WGK Germany
:
1
RTECS
:
WB6475000
F
:
8
HS Code
:
28276000
Hazardous Substances Data
:
7681-82-5(Hazardous Substances Data)
Safety
20
SSJCOE
Manufacture of Fluconazole
21
SSJCOE
Manufacture of Fluconazole
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 22
SSJCOE
Manufacture of Fluconazole
4.2.2 Synthesis of Fluconazole Triazole-1 yl) Acetophenone.
23
from
2,4-Difluoro-2-(1H-1,2,4-
SSJCOE
Manufacture of Fluconazole
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.
24
SSJCOE
Manufacture of Fluconazole
Material Balance? Energy balance? Thermodynamic feasibility?
25
SSJCOE
Manufacture of Fluconazole
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 ( Δ HR) is calculated as follows : Δ HR = (ΔHR)298 + ∫ ΔCP dT where ΔCP
=
∑(CP) PRODUCTS - ∑ (CP) REACTANTS
But (CP) PRODUCTS
=
(CP) REACTANTS
Thus, Δ HR = (ΔHR)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 .
26
SSJCOE
Manufacture of Fluconazole
A) 2,4-Difluoro-2-(1H-1,2,4-Triazole-1 yl) Acetophenone.
Functional Group
No of groups
Δ (Hj)298
Δ Hj
=N- (ring)
3
55.52
166.56
F-
2
-251.9
-503.8
=CH- (ring)
5
2.09
10.45
=C= (ring)
3
46.43
139.29
=C= (non ring)
1
83.99
83.99
O= (non ring)
1
-247.6
-247.6
=CH2 (non ring)
1
-20.64
-20.64
Hence, ΔH (DFTA)
=
∑, ΔHj + 68.29
=
-293.46 kcal/mol
B) Trimethyl Sulphoxinium Iodide Functional Group
No of groups
Δ (Hj)298
Δ Hj
-CH3 (non ring)
3
-76.45
-229.35
1
21.06
21.06
O= (any other)
1
-247.6
-247.6
1
41.87
41.87
I-
Hence, ΔH (TMSI)
=
∑ ΔHj + 68.29
=
-345.73 kcal/mol
27
SSJCOE
Manufacture of Fluconazole
C) 1H-1,2,4-Triazole
Functional Group
No of groups
Δ(Hj) 298
ΔHj
-N= (ring)
2
55.52
111.04
=NH (ring)
1
31.65
31.65
-CH= (ring)
2
2.09
4.18
ΔH (1H-1,2,4-Triazole)
Hence,
=
∑ ΔHj + 68.29
=
215.16 kcal/mol.
D) Fluconazole Funtional Group
No of groups
ΔHj298
ΔHj
F-
2
-251.9
-503.8
=N- (ring)
6
55.52
333.12
=C= (non ring)
1
82.23
82.33
OH-
1
-208
-208
=CH2 (non ring)
2
-20.64
-41.28
=CH- (ring)
7
2.09
14.63
=C= (ring)
3
46.43
139.29
Hence, ΔH (Fluconazole)
=
∑ ΔHj + 68.29
=
-115.52 kcal/mol
28
SSJCOE
E)
Manufacture of Fluconazole
Dimethyl Sulphoxide
Functional Group
No of groups
ΔHj298
ΔHj
-CH3
2
-76.45
-152.9
-S-
1
41.87
41.87
O=
1
-247.6
-247.6
Hence, ΔH(DMSO)
=
∑ ΔHj + 68.29
=
-290.34 kcal/mol.
=
-68.784 kcal/mol.
=
∑ΔH PRODUCTS
=
∑ [ΔHFLUCONAZOLE+ΔHDMSO+ΔHNAI]
F) Sodium Iodide ΔH ( NaI)
Thus, ΔHR
-
-
∑ΔHREACTANT
∑ [ ΔHDFTA+ΔHTMSI+ΔHTRIAZOLE]
=
-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 ΔH Where,
Tin
=
Heat gained by cooling water
=
m * Cp * ( T in – T out) …….. ( 1 )
=
5 ◦ C.
=
278 K
29
SSJCOE
Manufacture of Fluconazole
Cp Let‟s
=
Tout =
ΔH
=
4.187 KJ/ Kg K. 303 K (Kmole of DFTA reacted) * (ΔHR in KJ/Kmol)
=
0.966 * ( - 50.614 * 4.187)
=
-204.71 * 10 ^ 3 KJ
Thus, from above equation ( 1 ), value of mass of water required per batch can be obtained. Thus,
m
=
1955.67
kg
m
=
1.956
tons per batch
30
per batch
SSJCOE
Manufacture of Fluconazole
31
SSJCOE
Manufacture of Fluconazole
Chapter Equipment Design
Density of DFTA
=
1390 kg/m3
Density of H20
=
1000 kg/m3
Density of 1 H-1,2,4-Triazole
=
1394 kg/m3
Density of NaOH
=
2130 kg/m3
Density of TMSI
=
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
32
SSJCOE
Manufacture of Fluconazole
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
=
9.019 m3
Concentration in Feed
=
Moles / Volume
=
Mass / ( Molecular weight * Volume)
=
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
=
( π/ 4) * D2 H
=
(π/4) * (0.8 H) * H
H
=
2.618 m
D
=
2.094 m.
Thus, C ( DFTA)
C ( TMSI)
C ( NaOH)
C ( 1 H-1,2,4-Triazole)
Also, Total Volume Generally, D= 0.8 H Thus, Thus,
9.019
33
SSJCOE
Manufacture of Fluconazole
34
SSJCOE
Manufacture of Fluconazole
Chapter Mechanical Design
Design Pressure
=
3 kg/ cm2
=
0.3 N/ mm2
=
( P * di ) / ( 2 f J – P ) + c
=
( 0.3 * 2094) / ( 2 * 110 * 0.85 - 0.3) + 2
=
5.36 mm.
=
6 mm
A) Thickness of Shell : ts
Take
ts
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: 35
SSJCOE
Manufacture of Fluconazole
fL1 = P ( Di + t) / ( 4 t ) fL1
=
26.25 N/ mm2
b) Due to weight of the vessel and its contents for vertical vessel.
fL2
=
W/ (π * ( Di + t) t )
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,
c)
=
density * volume * 9.81
=
8000 * 9.019 * 9.81
=
707811.12 N
W
=
Wo + 0.15 W
W
=
813982.79 N
fL2
=
( 813982.79) / ( π * (2094 + 6 ) * 6 )
fL2
=
20.56 N/ mm2
=
0
Due to wind load. fL3
( No wind Load )
Thus resultant stress in the longitudinal direction : fLR
= 36
fL1 + fL2 + f L3
SSJCOE
Manufacture of Fluconazole
= fLR
26.25 + 20.56 46.81 N/mm2
=
3) Torsional stress
Torque on vessel
Stress due to torque
( fs )
=
37 kN m
=
37 * 10 ^ 6 N mm
=
2 T / ( π * Di * t * (Di + t))
=
Resultant stress i.e. fR
( 2 * 37 * 10 ^ 6 ) / ( π * 2094 * 6* 2100)
fS
= 0.893 N / mm2
fR
= √ ( fT 2 – f T * f LR + fLR 2 + 3 fs 2 )
= √ ( 52.52 – 52.5 * 46.81 + 46.82 + 3* 0.8932)
Hence , fR
=
58.69 N / mm2
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 37
SSJCOE
Manufacture of Fluconazole
=
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 :
Where,
But,
Th
=
( P Rc W ) / ( 2 f J)
Rc
=
Crown radius
=
2094 mm
W
=
stress intensification factor
W
=
(1/4) * ( 3 + √ ( Rc / Rk ) )
Rk
=
6 % of Rc
Rk
=
0.06 * 2094
=
125.64 mm.
W
=
(1/4) * ( 3 + √ ( 2094 / 125.64 ))
W
=
1.77
J
=
1 ( for head ) 38
SSJCOE
Manufacture of Fluconazole
Thus , we have
Th
=
( 0.3 * 125.64 * 1.77 ) / ( 2 * 110 * 1)
Th
=
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
=
Dso + 1.2
=
2230 mm.
=
( Pj Dij ) / ( 2 f J – Pj)
=
6
kg/ cm2
=
0.6
N/ mm2
= ( 0.6 * 2230 ) / ( 2 * 110 * 0.85 – 0.6 ) =
7.178 mm
=
10 mm.
Including corrosion allowance take trj
39
SSJCOE
Manufacture of Fluconazole
b) Jacket Closer Thickness It should be the higher value of the following : i)
=
2 * t rj
=
2 * 10
trc
=
20 mm
trc
=
0.866 * Wj √ ( Pj / f )
Here, Wj
=
Jacket width
ii)
But, Jacket width
=
trc
( Inside dia. Of Jacket – Outside dia. Of vessel) / 2 Wj
=
(2230 – 2110 ) / 2
Wj
=
60 mm.
Thus, trc
=
0.866 * 60 * √ ( 0.6 / 110 )
trc
=
3.84 mm
Hence, take higher value of trc , i.e. trc
=
20 mm.
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.
40
SSJCOE
Manufacture of Fluconazole
D) Design of Flange And Bolts
I)
Design of gasket.
Outer diameter of shell
Do
=
2110 mm.
Thus, Inner diameter of gasket
Gi
=
Do + 10
Thus, Inner Diameter of gasket
Gi
=
Do + 10
Gi
=
2120 mm.
( Go/ Gi)
=
√ ( ( y – pm) / ( y – p (m+1)))
Where, Go
=
outer diameter of gasket.
=
gasket seating stress.
=
11 N/ mm2
=
Gi * √ ( ( y – pm) / ( y – p (m+1)))
=
2151.25 mm.
Also,
Y
Thus ,
Go Go
Thus, width of the gasket
(N) = N
=
( 2151.25 – 2120) / 2
N
=
15.63 mm
=
N/2
=
15.63 / 2
=
7.814 mm.
Basic Gasket Seating width ( bo)
bo Now,
( Go – Gi ) / 2
as bo > 6.3 mm , efeective gasket seating width ( b) is given as : b
=
2.5 * √ (7.814)
b
=
6.988 ≈ 7 mm.
41
SSJCOE
Manufacture of Fluconazole
=
Go – 2 b
=
2151.25 - 2 ( 7 )
=
2137.25 mm.
=
πGby
=
π * 2137.25 * 7 * 11
=
517006.41 N
Wm2
=
π G * 2b * m * p + ( π/4) G2 * P
Wm2
=
1132672.07 N
Ab
=
Wm / ( fb ) = ( 1132672.07 / 53)
Ab
=
21371.17 mm2
But, Ab
=
n * ( π/4 ) * db 2
Diameter of gasket at load reaction ( G )
G II)
Design of Bolt :
Bolt load under atmospheric condition : Wm1
Wm1 Bolt load under operating conditions :
As Wm2 > Wm1, we take this value. Hence, area of bolt required is
Where, n
= no. of bolts.
n
=
G/ 25 =
n
=
86
n
=
88 ( multiple of 4 )
db
=
√ ( (4 * π) / ( A/ n ))
=
17.58 ≈ 18 mm.
Take Thus db
42
2137.25/ 25
SSJCOE
Manufacture of Fluconazole
Use M18 * 2 bolts, 88 numbers. Bolt circle diameter
(B)
=
Go + 2 db +12
B
=
2151.25 + 2 (18) + 12
B
=
2199.25 mm
Thus, B
=
2200 mm.
Actual bolt spacing required bs
=
πB/ n
=
(π * 2200 ) / 88
=
78.54 mm
=
B + 2 db+ 12
=
2200 + 2 ( 18) + 12
Dfo
=
2248 mm.
k
=
1 / ( 0.3 + 1.5 Wm hG / (HG) )
Wm
=
bs III)
Design of Flange
Outside diameter of the flange Dfo
where,
Max bolt load
=
1132672.07 N
=
(B - G) / 2
=
( 2200 – 2137.25) / 2
hG
=
31.38 mm.
H
=
(π/4) * G 2 P
hG
43
SSJCOE
Manufacture of Fluconazole
H
=
1076271.37
k
=
3.0943
=
G √ ( P/ k f)
=
2137.25 √ ( 0.3 / ( 3.0943 * 110 ))
Thus, Thickness of flange
tf tf
Thus,
tf =
63.45 mm ≈ 65 mm.
E) Nozzle Reinforcement Design Design Pressure
=
0.3 N / mm2
Diameter of nozzle
=
100 mm.
Material of nozzle is same as that of reactor. =
P Di / ( 2f J – P)
tn
=
( 0.3 * 100 ) / ( 2 * 110 * 1- 0.3)
tn
=
0.1365 mm.
≈
1 mm.
Thickness of nozzle ( tn)
Horizontal diameter for compensation AB
=
2 Dn
=
2 * 100
=
200 mm
=
6 * tn
Vertical Diameter for Compensation. We take the greater value of the following: i)
AD
44
SSJCOE
Manufacture of Fluconazole
=
6 * 3 = 18 mm.
=
3.5 * ts + 2.5 tn
=
3.5 * 8 + 2.5 * 3
AD
=
35.5
AD
=
35.5
=
100 * 8
=
800 mm2
Area of compensation provided by head
=
Din* ( ts – ts‟ )
Ah
=
100 * (8-6)
=
200
=
2 Ht * ( tn – tn „ –c)
=
2.5 * ts
=
2.5 * 8 = 20 mm.
=
3
=
0.1365
Ao
=
2 * 20 * ( 3- 0.1365 – 0 )
Ao
=
114.54 mm2
ii)
Take greater value , i.e.
AD
Area of Compensation
Area of compensation provided by nozzle Where, Ht
tn tn‟ Thus,
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
45
SSJCOE
Manufacture of Fluconazole
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 * ρ * N ^3 * Da^5) / (gc * 75)
Where ,
=
10 rpm
=
0.1667 rps
gc
=
9.81 m/ sec2
(Da)
=
1.01 m
Agitator Diameter
N
To find density of reaction mixture ( ρ ) Density of fluid entering the reactor
=
Mass / Volume
Where,
Mass
=
Mass ( Reactants + Water)
Volume
=
Volume (Reaction Mixture )
=
( 400 kg DFTA + 400 kg TMSI
Total mass of reactants
+ 160 kg 1 H-1,2,4-Triazole + 160 kg NaOH ) 46
SSJCOE
Manufacture of Fluconazole
Total mass of reactants
=
1120 kg.
Mass of Water
=
6000 kg
=
7120 kg.
=
6000/ 1000
=
6 m3
=
Mass/ Volume
=
400/1390
=
0.288 m3
=
160/2130
=
0.075 m3
=
400/ 1399
=
0.286 m3
=
160/ 1394
=
0.115 m3
=
Volume ( water + reactants )
=
6 + ( 0.764)
Hence, density of reaction mixture (ρ)
=
7120 kg/ 6.764 m3
ρ
=
1052.63 kg/m3
Thus,
total mass
Volume of water fed
Volume of DFTA fed
Volume of DFTA fed Similarly, Volume of NaOH fed
Volume of TMSI
Volume of 1 H-1,2,4-Triazole
Thus, Total Volume of Reaction Mixture
47
SSJCOE
Manufacture of Fluconazole
To find Power number Power number ( Np) can be approximated from a graph of log ( Np) v/s log ( NRe) NRe is Reynold‟s number. Nre
=
( ρ N Da^5 ) / μ
N
=
10 rpm for highly viscous fluid.
But, Let
The value of „ μ „ of reaction mixture is taken as the viscosity of Fluconazole suspension in water as gel. Thus ,
μ
=
Hence ,
Nre
=
Nre
=
2
Np
=
28
Hence , Power required for agitator ( P)
=
(Np * ρ * N ^3 * Da^5) / ( gc * 75 )
=
0.196 hp
From log Np v/s log Nre graph,
P
103.96 pascal sec. 1052.63 * 0.1667 * ( 1.01 )^5 / 103.96
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)
=
( P * 4500) * 10 ^4 / ( 2π N ) N mm.
=
(0.5 * 4500) * 10 ^4 / ( 2π * 10)
=
358098.62 N mm
=
1.5 Tr
=
537147.93 N mm.
48
SSJCOE
Manufacture of Fluconazole
a) But, Where, Thus,
Tm
=
(π / 16 ) * fs * d ^3
fs
=
125 N/ mm2 for SS 316.
=
(π/16) * 125 * d ^3
=
27.97 mm.
537147.93 d
b) This Tm is resisted by the „Fm‟ which acts at 75 % of max radius of impeller. Thus, Where,
But,
Fm
=
Tm / ( 0.75 * Rb)
=
radius of blade in mm.
=
505 mm
Fm
=
1418.21 N
Mm
=
Fm * L
Rb
Where „ L „ is shaft length between agitator and bearing.
Also, Where,
Hence,
Mm
=
1418.21 * 900
Mm
=
1276389 N mm
Mm
=
(π / 32) * fb * d^3
fb
=
bending stress
fb
=
230 N/ mm2 for S.S.
1276389
=
(π / 32) * 230 * d ^ 3
d
=
38.38 mm.
Also, by maximum shear stress theory, Equivalent twisting moment ( Te) is given as : Te
=
49
√ ( Mm2 + Tm2 )
SSJCOE
Manufacture of Fluconazole
Te Te
=
But,
=
√ ( 1276389 ^ 2 + 537147.93 ^ 2)
1.38 * 10 ^ 6 N/ mm2 Te
=
(π / 16) * fs * d^3
d
=
38.31 mm.
Also, by maximum normal stress theory , Equivalent Bending moment ( Me) :
Also,
Me
=
(1/2) * ( Mm + √ ( Mm ^ 2 + Tm ^ 2))
Me
=
1.33 * 10 ^ 6 N/ mm2
Me
=
( π/ 32) * fb * d ^3
=
( π/ 32) * 230 * d ^ 3
=
38.91 mm.
1.33 * 10 ^ 6 d
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.
50
SSJCOE
Manufacture of Fluconazole
Design of Centrifuge Top discharge with hydraulic power pack arrangement for lifting bag and lid.
Basket Diameter
D
=
1210 ± 5 mm
Thickness of basket
δ
=
6 ± 1 mm.
=
1650 mm.
Overall Height of basket
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
ω
=
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:
Where,
Pc
=
0.5 * ρ * ω^2 * ( b2 – a 2)
ρ
=
density of solids.
ω
=
angular velocity.
b
=
radius of basket.
a
=
radius of inner surface of solids
51
SSJCOE
Manufacture of Fluconazole
=
radius of basket – thickness of solid layer
=
0.605 - 0.1
a
=
0.505 m
ω
=
78.54 rad / sec
a
To find density of solids ( ρ ) : i)
Density of each species
Density of Fluconazole
=
1490 kg/ m3
Density of TMSI
=
1399 kg/ m3
Density of NaOH
=
2130 kg/m3
Density of DFTA
=
1390 kg/m3
Density of 1H-1,2,4-Triazole
=
1394 kg/m3
Density of DMSO
=
1100 kg/m3
Density of NaI
=
3670 kg/m3
ii)
No. of moles of each species in centrifuge:
Kmol of Fluconazole
=
0.947
Kmol of NaI
=
0.947
Kmol of DMSO
=
0.947
Kmol of DFTA
=
0.827
Kmol of TMSI
=
0.844
Kmol of 1H-1,2,4- Triazole
=
1.344
52
SSJCOE
iii)
Manufacture of Fluconazole
Mass of each species in centrifuge = kmol * molecular weight.
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)
=
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 fraction of each species
Fluconazole
=
0.265
NaI
=
0.13
DMSO
=
0.067
DFTA
=
0.169
TMSI
=
0.17
53
SSJCOE
Manufacture of Fluconazole
1 H-1.2.4-Triazole
=
0.088
NaOH
=
0.111
Hence, density of solids = average density of solids in the product mixture in centrifuge. i.e.ρ thus,
Hence,
=
∑ ρi xi
ρ
=
1773.31 kg/m3
Pc
=
0.5 * 1773.31 * ( 78.54) ^ 2 * (0.6^2 -
Pc
=
5.74 * 10^ 5 N / mm2.
0.505 ^2)
Also, stress ( f) in the basket walls is given as:
But,
f
=
( b/ δ) * ( Pc + ρm * δ * b * ω ^ 2)
f
=
110 N/ mm2 for SS 316
Above equation has only one unknown i.e. „ δ „ . Thus by substituting the values of the other variables in the above equation, we have 110 * 10 ^6
=
Thus, δ
=
(0.605/ δ) * ( 5.74 * 10 ^ 5 + δ ( 2.99 * 10^7))
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.
54
SSJCOE
Manufacture of Fluconazole
55
SSJCOE
Manufacture of Fluconazole
Fluconazole MSDS Section 1 Chemical Product and Company Identification Product Name
:
Fluconazole
Catalog Codes
:
SLF1666
CAS#
:
86366-73-4
RTECS
:
XZ4810000
TSCA
:
TSCA 8(b) inventory: No products were found.
CI#
:
Not available.
Synonym
:
Fluconazole; Diflucan
Chemical Name
:
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
:
C13-H12-F2-N6-O
Contact Information
:
Sciencelab.com, Inc.14025 Smith Rd. Houston, Texas 77396 US Sales: 1-800-901-7247
International Sales: 1-281-441-4400
56
SSJCOE
Manufacture of Fluconazole
Section 2 Composition and Information on Ingredients Name
CAS #
% by Weight
Fluconazole
86366-73-4
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
:
Not
available.
MUTAGENIC EFFECTS
:
Not available.
TERATOGENIC EFFECTS
:
Classified.POSSIBLE for human.
DEVELOPMENTAL TOXICITY
:
Not available. Repeated or prolonged exposure is not known to aggravate medical condition.
Section 4 First Aid Measures 57
SSJCOE
Manufacture of Fluconazole
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
:
Not available.
Section 5:
58
SSJCOE
Manufacture of Fluconazole
Fire and Explosion Data Flammability of the Product
:
May be combustible at high temperature.
Auto-Ignition Temperature
:
Not available.
Flash Points
:
Not available
Flammable Limits
:
Not available.
Products of Combustion
:
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
:
59
Not available.
SSJCOE
Manufacture of Fluconazole
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:
60
SSJCOE
Manufacture of Fluconazole
Keep container tightly closed. Keep container in a cool, well-ventilated area. Do not store above 25°C (77°F).
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:
61
SSJCOE
Manufacture of Fluconazole
Physical and Chemical Properties Physical state and appearance
:
Solid. (Crystalline solid.)
Odor
:
Not available.
Taste
:
Not available.
Molecular Weight
:
306.3 g/mole
Color
:
White.
pH (1% soln/water)
:
Not available.
Boiling Point
:
Not available.
Melting Point
:
Not available.
Critical Temperature
:
Not available.
Specific Gravity
:
Not available.
Vapor Pressure
:
Not applicable.
Vapor Density
:
Not available.
Volatility
:
Not available.
Odor Threshold
:
Not available.
Water/Oil Dist. Coeff.
:
Not available.
Ionicity (in Water)
:
Not available.
Dispersion Properties
:
Not available.
Solubility
:
Not available
Section 10: 62
SSJCOE
Manufacture of Fluconazole
Stability and Reactivity Data Stability
:
The product is stable.
Instability Temperature
:
Not available.
Conditions of Instability
:
Excess heat.
Substances
:
Not available.
Corrosivity
:
Not available.
Special Remarks on Reactivity
:
Not available.
Special Remarks on Corrosivity
:
Not available.
Polymerization
:
Will not occur.
Routes of Entry
:
Inhalation. Ingestion.
Toxicity to Animals
:
Acute oral toxicity (LD50): 1271 mg/kg
Incompatibility with various
Section 11: Toxicological Information
[Rat]. TERATOGENIC EFFECTS
:
Classified POSSIBLE for human.
Other Toxic Effects on Humans
:
Slightly hazardous in case of skin contact (irritant), of ingestion, of inhalation.
Special Remarks on Toxicity to Animals :
63
SSJCOE
Manufacture of Fluconazole
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. 64
SSJCOE
Manufacture of Fluconazole
BOD5 and COD
:
Not available.
Products of Biodegradation
:
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
65
SSJCOE
Manufacture of Fluconazole
States) Identification
:
Not applicable.
Special Provisions for Transport
:
Not applicable
:
TSCA 8(b) inventory:
Section 15: Other Regulatory Information Federal and State Regulations
No products were found. Other Regulations
:
Not available.
Other Classifications
:
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
:
1
Fire Hazard
:
1 66
SSJCOE
Manufacture of Fluconazole
Reactivity
:
0
Personal Protection
:
E
National Fire Protection Association (U.S.A.) Health
:
1
Flammability
:
1
Reactivity
:
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
:
Not available.
Other Special Considerations
:
Not available.
Created
:
10/09/2005 05:33 PM
Last Updated
:
06/09/2012 12:00 PM
67
SSJCOE
Manufacture of Fluconazole
68
SSJCOE
Manufacture of Fluconazole
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.
69
SSJCOE
Manufacture of Fluconazole
70
SSJCOE
Manufacture of Fluconazole
71
SSJCOE
Manufacture of Fluconazole
72
SSJCOE
Manufacture of Fluconazole
73
SSJCOE
Manufacture of Fluconazole
74
SSJCOE
Manufacture of Fluconazole
75
SSJCOE
Manufacture of Fluconazole
76
SSJCOE
Manufacture of Fluconazole
77
SSJCOE
Manufacture of Fluconazole
78
SSJCOE
Manufacture of Fluconazole
79
SSJCOE
Manufacture of Fluconazole
80
SSJCOE
Manufacture of Fluconazole
81
SSJCOE
Manufacture of Fluconazole
82
SSJCOE
Manufacture of Fluconazole
83
View more...
Comments
