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By: James Gillis, Keni Mallinen, Brenna Swift CHEE 450 Design Project.

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Presentation on theme: "By: James Gillis, Keni Mallinen, Brenna Swift CHEE 450 Design Project."— Presentation transcript:

1 By: James Gillis, Keni Mallinen, Brenna Swift CHEE 450 Design Project

2 Process Overview Insulin Crystallization Batch Crystallization Equipment Design Parameters Production Capacity Materials of Construction Suppliers and Costing Sterilization and Recovery Comparison to Alternative Unit Operations


4 Majority of pharmaceutical products marketed in crystalline forms high purity facilitates subsequent centrifugation and drying improves products aesthetics Insulin separation by precipitation using zinc chloride Rhombohedral, zinc hexamer crystal structure

5 Batch crystallizers Similar to stirred tank reactors

6 Conditions, reagents, and their interaction dictate crystallization rate, yield, size, morphology, etc. SuperPro parameters compared to conditions and reagents utilized in previous insulin crystallization procedures No measure of pH in SuperPro; extent of crystallization set manually at 90% ComponentFlow rate (kg/batch) Mass Comp. (%)Concentration (g/L) Stream S-168: Stream from Diafiltration Unit Operation Acetic Acid Insulin WFI Stream S-126: Charge Stream for Crystallization Tank Ammonium Acetate Zinc Chloride

7 Crystallization of insulin achieved by precipitation of insoluble zinc-hexamer in aqueous solution, complemented by temperature decrease Inlet Protein Concentration Amorphous precipitate forms if concentration is too high Temperature Crystallization begins at ambient temperature (25 o C) Cooling to 5 o C further decreases solubility pH Use ammonium acetate buffer to fix pH at approximately 6.1 Acetate anions also improve crystallization

8 Metal Ion Concentration Divalent metal ions (group 15 elements) mediate intermolecular contacts Zinc chloride- soluble in acetic acid, allows formation of zinc insulin hexamer (pictured) 0.08g zinc/g insulin Other Potential Solvents Addition of 10% (v/v) acetone Increase step growth kinetics of insulin crystals

9 Insulin (12.78 kg/batch) WFI ( kg/batch) Zinc Chloride (2.00 kg/batch) INPUTS Acetic Acid (2.22 kg/batch) Ammonium Acetate (1.13 kg/batch) OUTPUTS Acetic Acid (2.22 kg/batch) Zinc Chloride (2.00 kg/batch) Insulin (1.28 kg/batch) Ammonium Acetate (1.13 kg/batch) WFI ( kg/batch) Insulin Crystal (11.50 kg/batch) Total Mass Flow Rate = kg/batch Total Volumetric Flow Rate = L/batch Assumptions: Working volume is 75% of total tank volume Safety factor of 15% REQUIRED TANK SIZE = 270 L = 71 US gal

10 Complete economic analysis is necessary to find optimal operating throughput (number of batches) Capital and operating cost optimization for entire process Equipment considerations to prevent bottlenecks and downtime (batch and continuous units) Crystallization extent as a function of time for porcine insulin (adapted from Schlichtkrull, 1958)

11 304 SS316 SSCarbon Steel Acetic AcidD-Severe EffectB-GoodC-Fair Ammonium Acetate B-GoodA-ExcellentUnknown Zinc ChlorideB-Good D-Severe Effect Steel provides excellent strength, durability, and ease of cleaning/sterilization Three types of steel investigated for chemical compatibility with chemicals present in the inlet/outlet streams Carbon Steel Stainless Steel 304 Stainless Steel 316 Type 316 SS chosen as material of construction for crystallization tank Chemical Compatibility of Various Materials with Inlet Chemicals

12 Unsuccessful attempts to contact vendors Capital cost estimate using Matches online utility 270 L stainless steel crystallizer = $ 65, (2009 CAD) Approximate dimensions assuming H:D ratio of m diameter x 1.5 m height Adjusted 2007 USD cost using CEPCI and exchange rate of 0.80 USD/CAD Total cost of chemicals per batch: approximately $390 CAD/batch ($ with 10% v/v acetone) Potential suppliers: Solvias Inc. (Fort Lee, NJ), Paul Mueller Co. (Springfield, MI)

13 Crystal separation is achieved by basket centrifugation following V-106 Steam-in-place (SIP) sterilization between batches using saturated steam (15 psi, 121°C)

14 Several options available to obtain unique drug types or zinc free insulin: Gel filtration chromatography Ultrafiltration Diafiltration These units can successfully purify insulin, though a crystalline product would not be obtained Other common crystallization procedures include: Evaporative batch crystallization Adiabatic crystallization Continuously seeded crystallization Wide variety of reagents available and acceptable for insulin crystallization Use of phosphate & citrate buffers Crystallization of monomeric insulin analogs

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