Pharmaceutical Freeze Drying:
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1 Pharmaceutical Freeze Drying: The Lyophilization Process Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 1
2 Outline I. What is freeze drying? II. Reasons for freeze drying III. Steps in freeze drying A. Freezing B. Primary Drying C. Secondary Drying IV. Case Studies V. Pros and Cons of Freeze Drying Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 2
3 I. What is Freeze Drying? Definition of Freeze Drying To dry (as food) in a frozen state under high vacuum esp. for preservation (Webster Dictionary)... a means of drying, achieved by freezing the wet substance and causing ice to sublime directly to vapor by exposing it to a low partial pressure of water vapor (Sterile Pharmaceutical Manufacturing - Applications for the 1990 s) Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 3
4 II. Reasons for Freeze Drying? Material chemically unstable in solution Low temperature drying process Compatible with protein pharmaceuticals The amorphous form of the drug is desirable (i.e., solubility) Low particulate contamination Compatible with aseptic/sterile processing Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 4
5 Pharmaceutical Freeze Drying Involves: 1. Dissolving the drug and excipients in a suitable solvent, generally water. 2. Sterilizing the bulk solution by passing it through a bacteria-retentive filter. 3. Filling into individual sterile containers. 4. Freezing the solution by placing the open containers on cooled shelves in a freeze drying chamber or pre-freezing in another chamber. 5. Applying Vacuum to the chamber and heating the shelves in order to sublime ice. Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 5
6 Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 6
7 Desired Freeze Dried Characteristics Intact cake Sufficient strength Uniform color Sufficiently dry Sufficiently porous Sterile Free of Pyrogens Free of particulate Chemically stable Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 7
8 III. Steps in Freeze Drying A. Freezing Freezing of water into ice to produce a rigid frozen solute structure Solutes concentrate between ice crystals B. Primary Drying Removal of ice via sublimation Product temperature less than Collapse temperature C. Secondary Drying Remove adsorbed water Achieve moisture content needed for stability Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 8
9 Freeze Drying Equipment Chamber Condenser Condensing Coils Vacuum Pump Product Shelf Compressor Shelf Fluid Pump Heat Exchanger Heater Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 9
10 Steps in Freeze Drying 40 Shelf Temperature Mean Product Temperature 140 Temperature ( o C) Chamber Pressure Pressure (millitorr) -40 A B C Time (Hours) Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 10
11 Freeze Drying Temperature Time Pressure Solution Powder Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 11
12 A. Freezing Process Cooling Supercooling Ice Nucleation Crystal Growth A. Concentration of Solutes Ionic strength Reaction rates Precipitation of Buffers - ph shifts Metastable Amorphous B. Solute C. annealling Crystallization of solute (eutectic) D. Crystalline / Amorphous mixture Amorphous solute vitrification Lyotropic liquid crystals Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 12
13 Crystalline Solutes Some solutes crystallize with ice during freezing Crystalline solutes After Freezing (Freeze Concentrate) Eutectic Mixture The temperature where solute and ice both exist in a rigid crystalline state is the eutectic temperature. For example, NaCl forms a eutectic mixture containing 23.3%NaCl and melts at o C. Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 13
14 Amorphous Solutes Most solutes don t crystallize and form a random (amorphous) viscous glassy phase Amorphous solute After Freezing (Freeze Concentrate) Glassy Mixture In these systems the viscosity of solute phase increases until the solute is completely immobile and behaves like a glass. The temperature where the solute behavior changes from solution to a rigid glass is the glass transition temperature. Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 14
15 Physical State of the Solute and Temperature: Significant Impact on Freeze-Drying Behavior Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 15
16 Types of Freeze-Drying Behavior: Crystallization of Nafcillin During Annealing Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 16
17 B. Primary Drying The sublimation of ice from the frozen solution to create a dried layer of solute Solute must form a rigid structure to support its weight after the removal of ice. Maintaining product below the collapse temperature is critical to produce acceptable material Consequences of improper temperature control Collapse product Shrunken freeze dried plug Melt-back Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 17
18 Product Collapse - during freeze drying product temperature exceeds the collapse temperature and the material collapse as ice is sublimed. Fill volume Solute Ice After ice sublimed a dried residue of solute is produced. Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 18
19 Types of Freeze-Drying Behavior: Collapse Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 19
20 Example Of Collapse Annealed vs. Unannealed Sucrose/Glycine Formulations Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 20
21 Significance of Temperature Collapse temperatures are formulation dependent During Freeze Drying Primary drying (I.e., ice sublimation), Glass transition temperature, Tg T<<Tg Tg T>>Tg "Rigid" Solid Semi-solid "Fluid" Liquid Increasing molecular mobility & "reactivity" Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 21
22 How is Product Temperature Controlled during Primary Drying? Product temperature is controlled indirectly: a. Chamber pressure - Heat Transfer - Mass Transfer (Product Resistance) b. Shelf temperature - Heat Transfer Condensing coils T Freeze Dryer Shelf Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 22
23 Properly dried material produces a well formed cake with no apparent shrinkage. Important Points about Primary Drying Product temperature is critical during primary drying Changes in product temperature during drying may influence appearance of final product Damage which occurs during primary drying can not be repaired. Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 23
24 Freeze drying is a process where heat and mass transfer are coupled! P c m R p P o T i K v Ice Q Shelf Temp - T s T b Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 24
25 Influence of Vapor Flow Resistance on Product Temperature Water vapor must have enough energy to pass through the dried layer and to the condenser As resistance increases more energy (heat) is needed for water vapor to escape Product temperature increases with increasing resistance m Nitrogen Vacuum Interface Mass R p Dried Layer Ice/Produce Interface Ice Ice Heat Water vapor Heat Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 25
26 Why Does Product Collapse => Product Resistance Solution Frozen Product Heated Ice Sublimes (Heat Removed) Product Resistance Increases No Vapor Pressure Increases Dry? Yes No Is T > T c? Yes Temperature Increases Dry Cake Collapse Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 26
27 Heat and Mass Transfer Equations Describing Freeze Drying m = ( ) A ( P P ) A P P p o c R p + R s = p o c R p Eq. 1 where P c = chamber pressure/ (above dried solute) R p = product resistance R s =stopper resistance. m = rate of sublimation P o = vapor pressure of ice Relationship between chamber pressure and vapor pressure of ice (I.e., ice temperature) A v = surface of vial K v = vial heat transfer coefficient v v( S Δ I) T s = shelf temperature = = Eq. 2 ΔH ΔΗs ΔΗ s = enthalpy of sublimation s ΔT = temperature difference across ice slab T I = temperature at the ice interface m Q AK T T T Relationship between shelf temperature and ice temperature Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 27
28 The relationship between the vapor pressure of ice and ice temperature is TI = Eq. 3 ln P o Combining Eq. 1, 2, and 3 yields Eq. 4 R p = Kv Ts ΔT ΔΗ s ( P P) Ap A o c v ln o. ( P ) Eq. 4 Eq. 4 describes the relationship between product resistance, vapor pressure of ice (product temperature), the shelf temperature, and chamber pressure). Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 28
29 1000 Vapor Pressure of Ice (torr 10-3 ) A B 200 C Product Resistance (torr cm 2 hr gm -1 ) Regression analysis of vapor pressure of ice and product resistance data collected at a shelf temperature of 20 C and 100 millitorr (A), shelf temperature 0 C and 100 millitorr (B), and shelf temperature of -20 C and chamber pressure 80 millitorr with Eq. 4 assuming a 2 degree temperature gradient across the ice slab. Increase R p related to increase P o (i.e., Temperature) Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 29
30 C. Secondary Drying Removal of adsorbed water from the dried solute (no ice present) 5% water 0.1% water Controls moisture level in product to maintain proper chemical and physical stability. Reversible process (can de-humidify and humidify product to change moisture content) Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 30
31 Critical Points for Consideration Degradation Concentration effects during freezing Reconstitution Disperse material in freeze dried cake Collapse Glycine and mannitol bulking agents raise T c Damage during freezing and drying Cryoprotectants and lyoprotectants Stabilizers (amorphous) Sugars (sucrose, lactose), glycine Adherence to glass Surfactants, silicone Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 31
32 Critical Points for Consideration Physical state in frozen solution Excipient and active pharmaceutical ingredient Physical state in freeze dried powder Impact on physical and chemical stability Influence of processing conditions Changes in thermal history can changed the physical state of material(s) and effect process compatibility and chemical stability Understanding facilitates formulation development, process design and control Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 32
33 Case Study Nafcillin Sodium N. Milton and S. L. Nail. The physical state of nafcillin sodium in frozen aqueous solutions and freeze-dried powders. Pharmaceutical Development and Tech, 1 (3), , Buffers and ph control Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 33
34 Isothermal Crystallization Photomicrographs of 25% nafcillin sodium frozen solution using crossed polars and first order red compensator: A) frozen solution at -10 C, B) frozen solution at -4 C, C) frozen solution after 5 minutes at -4 C, and D) frozen solution after 15 minutes at -4 C. Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 34
35 Solid state decomposition at 50 C of nafcillin sodium unannealed (open symbols) and annealed (closed symbols) stored at 11% (squares) and 23% (triangles) relative humidity. Unannealed less stable than Annealed Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 35
36 Case Study - Buffer Selection Preliminary data suggested the optimal solution ph between 4-5 Formulations prepared with acetate, citrate and tartrate buffers All buffers were prepare in equal molar concentrations and adjusted with NaOH Acetate buffer least stable (Why?) Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 36
37 Effect of various Buffers on Stability (100 mm) % TRS Acetic acid Citric acid ph 4.0 Tartaric acid Time, (Weeks) % TRS ph 4.5 Acetic acid Citric acid Tartaric acid Time, (Weeks) Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 37
38 Review of Data ph of reconstituted acetate buffer formulation increased ph units Acetic acid component of buffer system Acetic acid is volatile and evaporates Loss of acetic acid leads to increase in formulation ph and poor stability Avoid use of volatile buffer species or other materials (I.e., ammonium salts) Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 38
39 Conclusions Advantages of Freeze Drying 1. Low particulate contamination 2. Solid more stable than solution 3. Low temperature process => less in-process degradation 4. Compatible with aseptic processing 5. Can be easily reconstituted Disadvantages of Freeze Drying 1. Cost => capital expenditures, process long and expensive 2. Difficult to produce crystalline material Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 39
40 Conclusions Freeze drying provides a method of drying temperature labile materials. The freeze drying process is divided into 3 steps: -Freezing - Primary Drying - Secondary Drying Changing the freezing, primary drying, or secondary drying conditions can influence the physical and chemical stability of the final product Freeze drying is often the last choice in methods for drying materials, because the cost and time required. Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 40
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