The Importance of Critical Temperatures in the Freeze Drying of Pharmaceuticals
Why are Critical Temperaturesimportant in freeze-drying?• Freeze-drying above the • Freeze-drying too far product critical below the product critical temperature can lead to: temperature can led to: – Loss of physical structure – Poor efficiency – Incomplete drying (high – High running costs moisture content) – Longer cycles than – Decreased solubility necessary – Reduced activity and/or stability
Critical Temperatures for freeze-drying• Collapse Temperature (Tc) – This is the temperature at which the material softens to the point of not being able to support its own structure• Eutectic Temperature (Teu) – This is the temperature at which the solute material melts, preventing any structure from forming after the solvent has been removed• All formulations can be described as having either a Collapse or a Eutectic Temprature.
Effect on formulation components oncritical temperature• Higher molecular weight components such as polymers tend to have higher critical temperatures• Lower molecular weight components such as salts and small sugars tend to have lower critical temperatures• Additionally, crystalline/amorphous mix can have a major impact on critical temperature: – Lactose + NaCl (1:1) Tc ≈ -30 C – Lactose + NaCl (1:0.3) Tc ≈ -45 C
Critical TemperatureDetermination• Using extensive knowledge and experience in the freeze-drying industry, BTL has developed two unique analytical instruments. These bring scientific understanding and a rational approach to freeze-drying cycle development: Lyostat3 Lyotherm2 Freeze-drying microscope DTA & Impedance Analyser
Lyostat3 – Freeze-dryingmicroscope• Enables real-time observation of the behaviour of your formulation during freeze-drying• Enables temperature control between -196 C and 125 C to an accuracy of 0.1 C• By observing the sample structure during drying as the temperature is raised, the exact point of collapse or eutectic melt can be observed under the microscope.
Lyotherm2 – DTA andImpedance Analyser• Provides and integrated Differential Thermal Analyser (DTA) and Electrical Impedance Analyser (zsinφ) capability in one instrument• Can measure critical events in the frozen material that are undetectable by standard thermal analysis techniques• Enables characterisation of the required freezing parameters that are essential to a successful freeze- drying cycle
Critical Temperature Application Cycle Development• From analysis of the product we can determine: – The maximum product temperature we can freeze-dry at before the product is damaged, allowing us to set the primary drying temperature with confidence – by Lyostat3 analysis – What events occur in the frozen state that affect the freezing stage of the cycle, allowing us to add in any thermal treatment steps such as annealing – by Lyotherm2 analysis
Case Study Product Cycle Development• A customer approached BTL with a product that was being freeze-dried using a cycle borrowed from another product• They were discarding a high percentage of each batch due to defects occurring during freeze- drying
Case Study Product Cycle Development1. Information was obtained on the critical temperatures and thermal behaviour of the product using Lyostat3 and Lyotherm22. This data confirmed the lack of suitability of the existing freeze-drying cycle3. Critical temperature information was used to create a ‘first approximation’ cycle, tailored to the needs of the product.4. Date from this cycle was used to design a more optimised cycle until a safe and efficient cycle was achieved, minimising cycle time without jeopardising product quality
Case Study Lyostat3 analysisSample dries well at -50 C, but collapse starts as the temperature is increased to -45.7 C. This can be identified by defects appearing in the dried materialAs the temperature increases to -39.6 C the structure continues to weaken and collapse becomes more evident
Case Study Lyostat3 analysisThe analysis is repeated but with an added heat annealing step – frozen to -50 C, warmed to -15 C and cooled back to -50 C. Defects don’t appear until -31.4 C upon dryingAs the temperature increases to -30.8 C the structure continues to weaken and collapse becomes more evident
Case Study Lyotherm2 analysis1. Exotherm in DTA and increase in Impedance indicating a stabilisation/rearrangement of the frozen structure2. Increase in downwards gradient of Impedance curve indicating a softening of the frozen material3. Onset of a sharp endotherm consistent with the melting of the ice4. Minimum Impedance indicating complete mobility within the solute structure
Case Study Interpretation of analytical results• From the results of these analyses, we can me the following deductions: – The inclusion of an annealing step resulted in an increase in the collapse temperature from -45.7 C to -31.4 C, as well as increasing the ice crystal size and networking – Therefore, the maximum allowable product temperature during sublimation (to avoid collapse) was raised by 14.3 C by annealing, thereby allowing drying at higher temperatures, for a more efficient cycle. The higher the product temperature, the faster the drying rate
Case Study Existing customer cycle – 70 hours 1 2 3+20 C A-15 C-40 C Tc = -45.7 C-50 C Shelf Product Chamber Temperature Temperature Pressure 1 – Freezing 2 – Primary Drying 3 – Secondary Drying A – Product at risk of collapse
Case Study BTL cycle – 42 hours (including annealing) 1 2 3 4+20 C-15 C Tc = -31.4 C-35 C-50 C Shelf Product Chamber Temperature Temperature Pressure 1 – Freezing 2 – Annealing 3 – Primary Drying 4 – Secondary Drying
Case Study Enlarged section of previous graph 3+20 C The Sublimation Cooling Effect The lowering of product temperature caused by the sublimation of ice-15 C Tc = -31.4 C-35 C-50 C Shelf Product Chamber Temperature Temperature Pressure 1 – Freezing 2 – Annealing 3 – Primary Drying 4 – Secondary Drying
Case Study The next steps• From the previous run, we now know: – The extent of sublimation cooling, allowing us to increase the shelf temperature & chamber pressure as high as possible whilst sublimation cooling keep the product temperature below Tc – When sublimation was complete in temperature probed samples – The physical appearance of the cakes produced by the cycle – Residual moisture was measured in the final product, in order to establish whether the extent of secondary drying was sufficient
Case Study End results• A freeze-drying cycle with increased efficiency, reduced costs and no product rejects• Another very happy customer!
What is BTL?• Biopharma Technology Ltd was set up in 1997 to provide an international service in all aspects of freeze-drying technology.• Our strength comes from a wealth of experience and knowledge of product formulation and process development, particularly in the field of pharmaceuticals and biotechnology.