Prediction of Unwanted Crystallization of Freeze-Dried Protein Formulations Using α-Relaxation Measurements
Abstract
:1. Introduction
2. Materials and Methods
2.1. Preparations of Formulations
2.2. Freeze-Drying Protocols
2.3. Residual Moisture Content
2.4. Differential Scanning Calorimetry
2.5. Isothermal Microcalorimetry (To Determine τβ)
2.6. Specific Surface Area
2.7. X-ray Powder Diffraction
2.8. Procedure to Correlate Crystallization with Relaxation Time τβ
3. Results
3.1. Macroscopic and Microscopic Appearance
3.2. Residual Moisture
3.3. Specific Surface Area (SSA)
3.4. Differential Scanning Calorimetry Results
3.5. X-ray Powder Diffraction
3.6. Isothermal Microcalorimetry
4. Discussion
4.1. Placebo Formulation Pre-Test
4.2. Protein-Containing Samples Equalized for Residual Moisture
- The freezing step influences the residual moisture directly by determining the pore size of the formulation [36,37]. Furthermore, the freezing step influences α-relaxation directly by changes in the amorphous phase as well as indirectly by the residual moisture. Both effects are independent from each other.
- The residual moisture influences the α-relaxation and crystallization directly by plastization of the solid phase [31]. The effect on α-relaxation and crystallization is proportional.
4.3. Protein-Containing Samples
4.4. Comparison of IMC and DSC as Methods for Crystallization Prediction
4.5. Influence of PS20 on Relaxation and Crystallization
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
RN | AN1.5 | AN3.0 | QN | CN | |
---|---|---|---|---|---|
Tg [°C] | 60.21 ± 0.04 | 60.09 ± 0.03 | 60.16 ± 0.04 | 72.03 ± 0.06 | 48.98 ± 0.08 |
Δcp [Jg−1K−1] | 0.55 ± 0.02 | 0.42 ± 0.05 | 0.52 ± 0.08 | 0.46 ± 0.04 | 0.51 ± 0.06 |
[Jg−1] | 19.21 ± 0.72 | 14.81 ± 1.76 | 18.18 ± 2.82 | 21.45 ± 1.90 | 12.33 ± 1.46 |
[Jg−1] | 11.02 ± 0.41 | 8.48 ± 1.01 | 10.42 ± 1.62 | 14.61 ± 1.29 | 4.62 ± 0.55 |
crystallization onset [°C] | 97.20 ± 2.57 | 100.10 ± 0.42 | 101.65 ± 0.25 | 119.90 ± 0.28 | 91.96 ± 1.10 |
crystallization energy [Jg−1] | 70.48 ± 0.95 | 66.47 ± 0.30 | 71.20 ± 7.71 | 62.66 ± 2.31 | 64.15 ± 1.09 |
RN | AN1.5 | AN3.0 | QN | CN | |
---|---|---|---|---|---|
Tg [°C] | 62.26 ± 2.73 | 64.10 ± 1.41 | 62.09 ± 2.74 | 66.20 ± 3.19 | 50.45 ± 2.67 |
Δcp [Jg−1K−1] | 0.52 ± 0.12 | 0.62 ± 0.02 | 0.560 ± 0.03 | 0.48 ± 0.07 | 0.52 ± 0.10 |
[Jg−1] | 19.23 ± 5.21 | 24.04 ± 0.95 | 20.73 ± 2.07 | 19.92 ± 3.79 | 13.14 ± 3.31 |
[Jg−1] | 11.49 ± 3.12 | 14.82 ± 0.58 | 12.35 ± 1.23 | 12.67 ± 2.41 | 5.40 ± 1.36 |
crystallization onset [°C] | 103.87 ± 5.53 | 106.15 ± 2.84 | 96.80 ± 1.31 | 99.23 ± 6.61 | 87.15 ± 1.10 |
crystallization energy [Jg−1] | 66.75 ± 1.54 | 74.32 ± 0.29 | 69.41 ± 1.00 | 68.74 ± 1.10 | 62.69 ± 1.10 |
RN | AN1.5 | AN3.0 | QN | CN | |
---|---|---|---|---|---|
Tg [°C] | 62.27 ± 2.93 | 60.19 ± 1.74 | 60.01 ± 2.47 | 64.05 ± 3.06 | 48.29 ± 3.11 |
Δcp [Jg−1K−1] | 0.54 ± 0.02 | 0.47 ± 0.03 | 0.57 ± 0.01 | 0.29 ± 0.01 | 0.44 ± 0.01 |
[Jg−1] | 20.20 ± 1.85 | 16.64 ± 1.54 | 20.04 ± 0.90 | 11.13 ± 0.92 | 10.14 ± 0.93 |
[Jg−1] | 12.07 ± 1.10 | 9.55 ± 0.88 | 11.45 ± 0.51 | 6.85 ± 0.57 | 3.61 ± 0.33 |
crystallization onset [°C] | 96.21 ± 2.83 | 84.05 ± 1.16 | 93.74 ± 0.26 | 88.01 ± 1.54 | 88.11 ± 2.86 |
crystallization energy [Jg−1] | 64.79 ± 0.04 | 57.62 ± 1.23 | 62.42 ± 1.23 | 60.85 ± 0.98 | 63.68 ± 3.02 |
RN | AN1.5 | AN3.0 | QN | CN | |
---|---|---|---|---|---|
Tg [°C] | 80.32 ± 0.04 | 84.14 ± 0.24 | 80.31 ± 0.42 | 84.14 ± 0.42 | 63.82 ± 0.70 |
Δcp [Jg−1K−1] | 0.30 ± 0.01 | 0.34 ± 0.10 | 0.31 ± 0.02 | 0.33 ± 0.02 | 0.40 ± 0.02 |
[Jg−1] | 16.71 ± 0.63 | 20.05 ± 5.97 | 16.76 ± 1.10 | 19.58 ± 1.28 | 15.37 ± 0.72 |
[Jg−1] | 12.18 ± 0.46 | 14.96 ± 4.46 | 12.21 ± 0.80 | 14.61 ± 0.96 | 9.43 ± 0.44 |
crystallization onset [°C] | † | † | † | † | † |
crystallization energy [Jg−1] | † | † | † | † | † |
RN | AN1.5 | AN3.0 | QN | CN | |
Tg [°C] | 104.46 ± 0.09 | 104.09 ± 0.04 | 104.08 ± 0.16 | 106.51 ± 0.23 | 100.11 ± 0.11 |
Δcp [Jg−1K−1] | 0.46 ± 0.07 | 0.47 ± 0.01 | 0.41 ± 0.01 | 0.41 ± 0.02 | 0.52 ± 0.01 |
[Jg−1] | 36.59 ± 5.37 | 36.82 ± 0.97 | 32.06 ± 0.89 | 33.66 ± 1.70 | 39.36 ± 0.79 |
[Jg−1] | 29.68 ± 4.36 | 29.83 ± 0.78 | 25.98 ± 0.72 | 27.47 ± 1.39 | 31.50 ± 0.64 |
crystallization onset [°C] | † | † | † | † | † |
crystallization energy [Jg−1] | † | † | † | † | † |
Appendix B
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Excipient | 2 mg/mL 00PS_Suc | 2 mg/mL 04PS_Suc | 2 mg/mL 16PS_Suc | 50 mg/mL 16PS_Suc | 2 mg/mL 04PS_Tre |
---|---|---|---|---|---|
LMU1 | 2 | 2 | 2 | 50 | 2 |
sucrose | 79.45 | 79.45 | 79.45 | 79.45 | - |
trehalose | - | - | - | - | 79.45 |
PS20 | - | 0.4 | 1.6 | 1.6 | 0.4 |
Process | Step Number [#] | Shelf Temperature [°C] | Hold Time [h] | Ramp Rate of the Shelf towards the Next Step [K/min] |
---|---|---|---|---|
RN | 1 | 20 | - | −1 |
2 | −5 | 1.00 | −1 | |
3 | −45 | 1.50 | * | |
AN1.5 | 1 | 20 | - | −1 |
2 | −5 | 1.00 | −1 | |
3 | −45 | 1.50 | +1 | |
4 | −20 | 1.50 | −1 | |
5 | −45 | 1.50 | * | |
AN3.0 | 1 | 20 | - | −1 |
2 | −5 | 1.00 | −1 | |
3 | −45 | 1.50 | +1 | |
4 | −20 | 3.00 | −1 | |
5 | −45 | 1.50 | * | |
CN | 1 | 20 | - | −1 |
2 | −5 | 1.00 | † | |
3 | −5 | 2.00 | −1 | |
4 | −45 | 1.50 | * | |
QN | 1 | 20 | - | quenching |
2 | −196 ‡ | 0.03 | - | |
3 | −45 | 1.500 | * |
Excipient | 2 mg/mL 00PS_Suc | 2 mg/mL 04PS_Suc | 2 mg/mL 16PS_Suc | 50 mg/mL 16PS_Suc | 2 mg/mL 04PS_Tre |
---|---|---|---|---|---|
RN | 1.04 ± 0.03 | 0.84 ± 0.06 | 0.70 ± 0.06 | 0.31 ± 0.02 | 0.28 ± 0.05 |
AN1.5 | 0.90 ± 0.02 | 0.77 ± 0.07 | 0.85 ± 0.13 | 0.39 ± 0.04 | 0.36 ± 0.02 |
AN3.0 | 0.85 ± 0.00 | 0.93 ± 0.04 | 0.85 ± 0.01 | 0.35 ± 0.02 | 0.33 ± 0.03 |
QN | 0.41 ± 0.04 | 0.49 ± 0.14 | 0.55 ± 0.02 | 0.17 ± 0.06 | 0.13 ± 0.01 |
CN | 1.45 ± 0.10 | 1.42 ± 0.12 | 1.35 ± 0.02 | 1.34 ± 0.01 | 1.59 ± 0.22 |
Process | Original | Moisture Equilibrated |
---|---|---|
RN | 0.70 ± 0.06 | 1.30 ± 0.14 |
QN | 0.55 ± 0.02 | 1.15 ± 0.16 |
CN | 1.35 ± 0.02 | 1.36 ± 0.12 |
Excipient | 2 mg/mL 00PS_Suc | 2 mg/mL 04PS_Suc | 2 mg/mL 16PS_Suc | 50 mg/mL 16PS_Suc | 2 mg/mL 04PS_Tre |
---|---|---|---|---|---|
RN | 0.455 | 0.552 | 0.563 | 0.714 | 0.665 |
AN1.5 | 0.404 | 0.594 | 0.549 | 0.747 | 0.739 |
AN3.0 | 0.528 | 0.574 | 0.506 | 0.726 | 0.616 |
QN | 1.080 | 0.982 | 0.914 | 2.270 | 0.982 |
CN | 0.328 | 0.313 | 0.241 | 0.157 | 0.389 |
Excipient | 2 mg/mL 00PS_Suc | 2 mg/mL 04PS_Suc | 2 mg/mL 16PS_Suc | 50 mg/mL 16PS_Suc | 2 mg/mL 04PS_Tre |
---|---|---|---|---|---|
RN | 60.21 ± 0.04 | 62.26 ± 2.73 | 62.27 ± 2.93 | 80.32 ± 0.04 | 104.46 ± 0.09 |
AN1.5 | 60.09 ± 0.03 | 64.10 ± 1.41 | 60.19 ± 1.74 | 84.14 ± 0.24 | 104.09 ± 0.04 |
AN3.0 | 60.16 ± 0.04 | 62.09 ± 2.74 | 60.01 ± 2.47 | 80.31 ± 0.42 | 104.08 ± 0.16 |
QN | 72.03 ± 0.06 | 66.20 ± 3.19 | 64.05 ± 3.06 | 84.14 ± 0.42 | 106.51 ± 0.23 |
CN | 48.98 ± 0.08 | 50.45 ± 2.67 | 48.29 ± 3.11 | 63.82 ± 0.70 | 100.11 ± 0.11 |
Process | 2 mg/mL 00PS_Suc | 2 mg/mL 04PS_Suc | 2 mg/mL 16PS_Suc | 50 mg/mL 16PS_Suc | 2 mg/mL 04PS_Tre | |||||
---|---|---|---|---|---|---|---|---|---|---|
25 °C | 40 °C | 25 °C | 40 °C | 25 °C | 40 °C | 25 °C | 40 °C | 25 °C | 40 °C | |
RN | - | - | - | - | X | X | - | - | - | - |
AN1.5 | - | - | - | - | X | X | - | - | - | - |
AN3.0 | - | - | - | - | X | X | - | - | - | - |
QN | - | - | - | - | X | X | - | - | - | - |
CN | - | - | - | X | X | X | - | - | - | - |
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Groël, S.; Menzen, T.; Winter, G. Prediction of Unwanted Crystallization of Freeze-Dried Protein Formulations Using α-Relaxation Measurements. Pharmaceutics 2023, 15, 703. https://doi.org/10.3390/pharmaceutics15020703
Groël S, Menzen T, Winter G. Prediction of Unwanted Crystallization of Freeze-Dried Protein Formulations Using α-Relaxation Measurements. Pharmaceutics. 2023; 15(2):703. https://doi.org/10.3390/pharmaceutics15020703
Chicago/Turabian StyleGroël, Sebastian, Tim Menzen, and Gerhard Winter. 2023. "Prediction of Unwanted Crystallization of Freeze-Dried Protein Formulations Using α-Relaxation Measurements" Pharmaceutics 15, no. 2: 703. https://doi.org/10.3390/pharmaceutics15020703