Safety-Oriented Design of Tetrazole Synthesis in Pharmaceutical Manufacturing

Safety-Oriented Design of Tetrazole Synthesis in Pharmaceutical Manufacturing

Srikanth Reddy Jonnala

Department of Research and Development Lee Pharma Limited

Visakhapatnam, Andhra Pradesh, India

Abstract – The Formation of Tetrazoles is from Nitriles and Sodium Azide. The reaction Mechanism, Can Proceed through Different Pathways depend on the Reaction Conditions. Generally, it Involves the Activation of nitriles Followed by a

Nucleophilic Attack of the Azide ion (N -) as RCN + NaN

readily vaporizes, liberating a highly toxic, colorless, and explosive gas [13]. Here the Thermodynamic properties are Considered as a Safety Module. Before an explosion we Must Take a Safety precautionary Action. The Major Issue in This

Tetrazole Formation is Liberat ion of Hydrazoic Acid (HN )

3 3 3

3

Here in Sodium Azide having N – Electrons Having attack with Carbon then it is clearly azide attack on Nitrile Carbon to Formation of Tetrazole. This is Mostly Performed at Higher Temperatures and having a Significant in Pharmaceutical Drug Practices. This Reaction in Industrial scale having Explosion Hazard Chemicals like Sodium Azide as Thermally unstable with Regular Practice can leads a Explosive.so Better Practices makeup Development in Laboratory Scale through Optimum Temperatures ranges and Quenching Factors with Acids can Create a High Gas Liberation impact by Safe Approaching of this Preparation with Slow Addition Rate can Control the Reaction Rate in Large scale. These strategies enhance safety while maintaining efficiency, Venting Calculating approach, Proper Scrubbing media in Industrial Scale.

Keywords: Tetrazole Synthesis, Sodium Azide, Hydrazoic Acid,

1. INTRODUCTION

   Heterocyclic compounds form the backbone of modern drug discovery, with tetrazoles. A tetrazole ring consists of a five- membered heterocycle containing four nitrogen atoms and one carbon atom. Historically, strong mineral acids (such as sHCl or HSO) were employed for this protonation. This strategy introduces severe operational hazards [3], as strong acids violently displace the sodium cation to liberate hydrazoic acid (HN) gas [13]. Hydrazoic acid is notoriously toxic upon inhalation and highly unstable, carrying a severe risk of spontaneous vapor-phase detonation when heated or concentrated in reaction [11]. To resolve these pressing safety concerns without compromising chemical yield, specifically triethylamine hydrochloride (TEAHCl). The triethylammonium cation acts as a mild, buffered proton donor that establishes a steady, controlled equilibrium in solution that Refers the Chemical Equation:

   (C2H5)3NH+Cl- (aq) + NaN3-(aq) HN3(g) + (C2H5)3N+

   When hydrochloric acid is mixed with sodium azide it undergoes an acid-base displacement reaction that generates hydrazoic acid Hydrazoic acid is a highly volatile liquid that

   Gas with highly Volatile and ready to Vaporizes into Colorless Gases [6].

   Molecular weight=43.03g/mol Boiling Point: 37°C

   Melting point: -80°C

   Density: 1.09 g/cm3 at 25°C

   Standard Enthalpy of Formation ( f H): +294 kj/mol This highly positive heat of formation indicates that the molecule is thermodynamically unstable [5].

2. LITERATURE REVIEW:

   1. Historical Context:

      In their seminal 1958 work, Finnegan, Henry, and Lieber (J. Am. Chem. Soc.) established the baseline method for this condensation using sodium azide (NaN) paired with ammonium chloride (NHCl) as an acidic promoter in N,N-dimethylformamide (DMF) as Solvent [14].

      No, of Moles

      1.2204 k. mole

      1.107 k.mole

      0.263 k.mole

      0.263 k.mole

   2. Comparison Of Alternative Methods:

      Method	Reagents	Advantages	Disadvantages
      Finnegan Method	NaN3+NH4Cl	Cheap, Fast Reaction Rates	High Explosion Risk
      Amine Salt	NaN3 +TEA. HCL	Safe to Scaleup	Generate Small Amount of Volatile NH3
      Lewis Acid	NaN3+ZnCl2 +AlCl3	Neutralize the NH3 Gas	Requires Heavy Metals
      Silicon Azides	TMS-N3/ Fluoride Catalyst	No Metal Salts Required	Extremely Expensive Reagents, Water Sensitive

   3. Conclusion:

   This literature review contextualizes the TEA HCl protocol as the direct solution to the historical safety hazards. The combination of TEAHCl and NaN remains a good Methods in modern Industrial chemical process [4]. It cleanly Gives a balance between operational Easier, high conversion yields, and enhanced thermal process safety, making it a staple strategy for Large Scale Synthesis.

3. METHODOLOGY

   1. Estimation of HN3 Generation:

      Before Getting into Technical Calculation initially we Start with Mole For Our Basical Reaction for that we have Limiting reagent is Sodium Azide that I Takes as a Reference to Calculate this generation of Byproduct Quantities.

      (C2H5)3NH+Cl- + NaN3- HN3 + (C2H5)3N+

      	(C2H5)3NH+Cl-	NaN3-	HN3	(C2H5)3N+
      Weight	168 Kg	72 Kg	47.63 Kg	112.017 kg
      Mol.wt	137.65 g/Mol	65.009 g/mole	43.029 g/mole	101.19 g/mole

      Here one More Important thing is after Completion of reaction we must surely check Measuring Residual Sodium Azide (NaN3) in Reaction Mass. That we want to check in Ion Chromatography because it directly measures the azide ion with good accuracy.

   2. Gas Release Rate Determination:

      Here that I Estimated HN3 Gas 47 Kgs is Release Rate is 5 Minutes. So, Flowrate is 47 Kgs/ 5 Min = 9.4 Kg/Min then Convert into Kg/Sec = 9.4 Kg/60 = 0.1566 Kg/sec

      • Pressure (P)= (101,325 Pa) (Atmospheric pressure)

      • Gas Constant (R)= 8314 J/(kmol.K)

      • Molecular Weight(M) = 43.03 g/mol

   3. Gas density Estimation:

      Here we Have to Estimate in the Gas Density By using IDEAL GAS EQUATION:

      = P×M / R×T

      =(101,325 pa×43.03 g/mol) /(8314 j/(kmol.K) × 368 K

      = 1.42 kg/m3

   4. Minimum Vent Area Calculation:

      Volumetric Flowrate (Q):

      Q = W/

      = (0.1566 Kg/sec) / (1.42 kg/m3)

      Q = 0.11032 m3/Sec

      Calculate Minimum Vent Cross Sectional Area:

      Area (A) = Q / V

      Area (A) = (0.11032 m3/Sec) / (15 m/s)

      Area (A) = 0.007354 m2

      Calculate Inner Diameter:

      Area(A) = × D2 / 4 D2 = 4×Area /

      D = 0.0967 m D = 96.74 mm

      Convert into Inch 96.74 mm × 0.03937 = 3.80

      Then Prefer 4 Vent Line Is Required fir this Reaction.

   5. Neutralization of HN3 Content with safety Precautionary Action:

      After Completion of Reaction conversion and form tetraole Ring. Then there a Chance For HN3 Traces in Reaction Mass Because This reaction converts volatile, acidic HN into its ionic form (azide ion, N) in alkaline solution. In industrial settings, maintaining an alkaline environment helps reduce the amount of HN present in solution [2]. The Practical Solution Behind for this Problem is Improving the NaoH Workup Here Tetrazoles are acidic compounds [1]. When NaOH is added,

      HCT-405 (SS) (1.0 KL)

      Scrubber Line

      Scrubber Line

      Air Line

      Air Line

      Scrubbing System

      Vapour Coloumn

      RT OUTLET

      25 m2 RT INLET

      12"

      12"

      RT OUTLET

      Blower Vent

      RT INLET CHILLED OUTLET

      10 m2

      CHILLED OUT

      2"

      2"

      2"

      12"

      Chilled Out

      Chilled Out

      CHILLED INLET

      CHILLED IN

      Chilled Out

      6 m2

      6m2

      6m2

      Chilled In

      Chilled In

      6"

      12"

      SSR-1 (8 KL)

      SSR-2 (3 KL)

      2"

      Vaccum-1 Line

      Vaccum-1 Line

      Vaccum-2 Line

      1"

      1"

      1"

      2"

      2"

      Common Line For Collection

      Common Line For Collection

      2"

      H2O + Lye Solution

      2" H2O + Lye Solution

      2" H2O + Lye Solution

      Circulation Pump

      10 m3/Hr

      Circulation Pump

      10 m3/Hr

      Circulation Pump

      10 m3/Hr

      Collection Recievers

      Collection Recievers

      Trap

      Water JET Vaccum Pump: Capacity:

      Vaccum-2 Line

      Nitrogen Line

      Nitrogen Line

      Fig.1 Industrial Scale Piping & Instrumentation Diagram

      the tetrazole is converted to its tetrazole sodium salt, which is generally much more soluble in the aqueous phase than in toluene. This allows it to be separated from neutral organic impurities. In a later step, the product may be acidified again to regenerate the free tetrazole, if required. Any remaining HN is converted by NaOH into sodium azide [8].

      HN3 + NaOH NaN3 + H2O

      Sodium azide is highly water-soluble, so it partitions into the aqueous phase. his step reduces the amount of volatile HN in the reaction mixture.

      Here there having a Chance by Forming of Nacl Salts that mostly dissolves in Aqueous Layer. Finally Process Safety Concerns are Performed for Maintaining alkaline conditions minimizes the presence of volatile HN[10] , reducing the risk of hazardous vapor formation during work-up.

   6. Requirement of Scrubber:

      Before Getting into the calculation I Previously Mentioned That Flowrate Estimation is m=0.1566 Kg/sec and gas Density is Calculated by using Ideal Gas equation is =1.42 Kg/m3

      Calculation: Q=m/

      Q = 0.1566 Kg/sec / 1.42 Kg/m3 Q = 0.1103 m3/sec

      Then Convert into Kg/sec:

      Q = 0.1103 Kg/Sec × 3600

      Q = 397 m3/Hour

      Then Convert into CFM:

      CFM= 397 m3/Hour × 0.588

      CFM = 233.43

      Then finally we Have requirement of 233 CFM of Scrubber

   7. NaOH Requirement:

      HN3 + NaOH NaN3 + H2O

      Moles of HN3:

      n = 47000 g/43.03 g/mol n = 1092.26 mol

      NaOH Required= 1092.26 mol × 40 g/mol

      =43680 g.

      Convert in Kgs is 43.68 Kgs

      Here I Take 25% if Excess Quantity Required Quantity= 43.68 kg × 1.25 Required Quantity NaOH= 54.6 Kgs

   8. Estimation of Lye Solution Volume in Scrubber: Generally, in Industrial Cases we prepare 10% of NaOH Solution.

   Required Quantity of NaOH= 54.6 Kgs Solution Required = 54.6 /0.10

   Solution Required = 546 kgs Since the Density = 1.11 kg/L

   Solution Volume (V) = 546 kg/1.11 kg/L Solution Volume (V) = 491.85 L

   Here Recommendation is

   500 L of 10 wt.% NaOH solution

4. RESULTS & GRAPHS:

   Parameter	Value
   HN3 Generated	47 Kg
   Gas Release Time	50 min
   Mass Flowrate	9.4 Kg/min
   Gas Density	1.42 Kg/m3
   Volumetric Flowrate	0.1103 m3/sec
   Required Vent Area	0.00735 m2
   Calculated Diameter	96.77 mm

   1. Vent Sizing Results:

      Recommended Vent Size

      4 Inch

   2. Scrubber Design Results:

      Parameter	Value
      Gas	Hydrazoic Acid
      Total HN3 Released	47 Kgs
      Release Time (Estimation)	5 Min
      Gas Release Rate	9.4 Kg/min
      Operating Pressure	1 atm
      Operating Temperature	95°C
      Molecular Weight	43.03 /mol

   3. Overall Process Comparison:

   Parameter	Convectional (HCL/NH4Cl)	Proposed (TEA.HCL)	Improvem ent
   HN3 Released	High	Controlled	High
   Max Temperature	110°C	70°C	Excellent
   Vent Size	6	4	Good
   NaoH Required	High	54.6 Kg	Good
   Scrubber Effiency	90-95%	99%	Excellent
   Overall Safety	Low	High	Excellent

5. REFERENCES

1. Finnegan, W. G., Henry, R. A., and Lieber, E., "A New Synthesis of Tetrazoles," Journal of the American Chemical Society, vol. 80, no. 15,

   pp. 39083911, 1958.

2. March's Advanced Organic Chemistry, 7th ed., Wiley, 2013.

3. Comprehensive Heterocyclic Chemistry III, Vol. 5, Elsevier, 2008.

4. National Institute for Occupational Safety and Health, Hydrazoic Acid (HN): Pocket Guide to Chemical Hazards.

5. Occupational Safety and Health Administration, Hydrazoic Acid Safety Data and Occupational Exposure Information.

6. National Fire Protection Association, NFPA 68: Standard on Explosion Protection by Deflagration Venting, Latest Edition.

7. National Fire Protection Association, NFPA 69: Standard on Explosion Prevention Systems, Latest Edition.

8. American Society of Mechanical Engineers, ASME Boiler and Pressure Vessel Code, Section VIII Pressure Relief Devices.

9. American Institute of Chemical Engineers, Guidelines for Pressure Relief and Effluent Handling Systems, Center for Chemical Process Safety (CCPS).

10. American Institute of Chemical Engineers, Guidelines for Hazard Evaluation Procedures, 3rd ed.

11. Perry's Chemical Engineers' Handbook, 9th Edition, McGraw-Hill Education.

12. National Institute of Standards and Technology, NIST Chemistry Webbook: Hydrazoic Acid Physical and Thermodynamic Properties.

13. PubChem, "Hydrazoic Acid (HN)," National Library of Medicine.

14. Bretherick's Handbook of Reactive Chemical Hazards, 8th Edition, Elsevier.

15] Center for Chemical Process Safety, Layer of Protection Analysis: Simplified Process Risk Assessment.