The Impact of a Manufacturing Process on the Stability of Microcrystalline Long-Acting Injections: A Case Study on Aripiprazole Monohydrate
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Batch Preparation Processes
2.2.1. Preparation of Vehicle
2.2.2. Vehicle Autoclaving
2.2.3. Preparation of Primary Suspension
2.2.4. Preparation of Secondary Suspension
2.2.5. Freeze-Drying
2.2.6. Sampling
2.2.7. Batch Manufacturing Conditions and Naming
2.3. Analytical Methods
2.3.1. Particle Size Distribution (PSD) Analysis
2.3.2. Viscosity Analysis
2.3.3. CMCNa Molecular Mass Determination
2.3.4. X-Ray Powder Diffraction (XRPD) Analysis
2.3.5. Optical Microscopy
2.3.6. Stability Study
2.4. Statistical Analysis
3. Results
- tn—total time of milling for the n-th sample [min];
- ṁ—mass flow rate [g/min];
- msusp,n—mass of the remaining suspension at the n-th sample, accounting for the total mass of previous samples [g].
- N—theoretical passages;
- a, b—fitting parameters.
4. Discussion
5. Conclusions
6. Patents
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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AMDS Batch Name 1 | AMDP Batch Name 2 | Vehicle Thermal Treatment | Homogenization During Bead Milling | Homogenization After Bead Milling |
---|---|---|---|---|
AMDS-1 | AMDP-1R | N | N | N |
AMDP-1H | Y | |||
AMDS-2 | AMDP-2R | N | Y | N |
AMDP-2H | Y | |||
AMDS-2 | AMDP-3R | Y | N | N |
AMDP-3H | Y | |||
AMDS-3 | AMDP-4R | Y | Y | N |
AMDP-4H | Y |
AMDS Batch Name | Dv10 [µm] | Dv50 [µm] | Dv90 [µm] |
---|---|---|---|
AMDS-1 | 24 | 166 | 467 |
AMDS-2 | 22 | 192 | 548 |
AMDS-3 | 9 | 55 | 215 |
Thermal Treatment Duration [min] | Mn [kDa] | Mw [kDa] | Mz [kDa] | PDI (Mw/Mn) | PDI (Mz/Mn) |
---|---|---|---|---|---|
0 | 40.5 (± 1.6) | 60.8 (±3.5) | 96.6 (±10.6) | 1.50 (±0.06) | 2.39 (±0.23) |
15 | 41.1 (±2.8) | 62.3 (±3.0) | 103.7 (±6.3) | 1.52 (±0.03) | 2.52 (±0.07) |
22 | 39.1 (±1.8) | 60.4 (±1.3) | 99.6 (±2.7) | 1.54 (±0.05) | 2.55 (±0.14) |
30 | 39.6 (±1.2) | 60.5 (±2.8) | 99.9 (±10.3) | 1.53 (±0.04) | 2.52 (±0.20) |
60 | 40.1 (±1.9) | 59.4 (±1.5) | 95.5 (±3.6) | 1.48 (±0.04) | 2.39 (±0.13) |
Manufacturing Process | Dv10 [µm] | Dv50 [µm] | Dv90 [µm] | Dv99 [µm] | Dv100 [µm] | D[4;3] [µm] |
---|---|---|---|---|---|---|
AMDP-1 | 1.75 (±0.04) | 7.31 (±0.25) | 29.9 (±0.8) | 54.7 (±0.2) | 80.8 (±2.9) | 12.1 (±0.3) |
AMDP-2 | 1.74 (±0.07) | 8.51 (±0.35) | 34.5 (±1.1) | 62.7 (±1.1) | 92.6 (±3.3) | 14.0 (±0.5) |
AMDP-3 | 1.86 | 7.49 | 30.3 | 57.1 | 85.6 | 12.4 |
AMDP-4 | 1.60 (±0.07) | 7.77 (±0.76) | 31.8 (±1.9) | 56.4 (±2.5) | 81.8 (±3.1) | 12.9 (±0.9) |
Process | Stage | Dv10 [µm] | Dv50 [µm] | Dv90 [µm] | D[4;3] [µm] | Viscosity [mPa·s] | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
R 1 | H 1 | R 1 | H 1 | R 1 | H 1 | R 1 | H 1 | R 1 | H 1 | ||
AMDP-1 | pre-lyo | 1.30 (±0.09) | 1.21 (±0.07) | 3.81 (±0.12) | 3.36 (±0.08) | 10.05 (±0.49) | 8.37 (±0.31) | 4.93 (±0.21) | 4.30 (±0.08) | - 3 | - 3 |
post-lyo | 1.25 (±0.08) | 1.20 (±0.06) | 3.50 (±0.10) | 3.30 (±0.07) | 9.36 (±0.40) | 8.25 (±0.28) | 4.61 (±0.17) | 4.27 (±0.06) | 14.5 (±0.2) | 13.3 (±0.3) | |
AMDP-2 | pre-lyo | 1.31 (±0.01) | 1.29 (±0.02) | 3.46 (±0.09) | 3.51 (±0.11) | 9.27 (±0.38) | 9.40 (±0.53) | 4.65 (±0.13) | 4.73 (±0.20) | - 3 | - 3 |
post-lyo | - 2 | 1.30 (±0.02) | - 2 | 3.41 (±0.11) | - 2 | 9.34 (±0.61) | - 2 | 4.69 (±0.21) | - 2,3 | 12.5 (±0.4) | |
AMDP-3 | pre-lyo | 1.46 | 1.37 | 3.62 | 3.39 | 9.06 | 8.58 | 4.63 | 4.49 | - 3 | - 3 |
post-lyo | 1.40 | 1.35 | 3.42 | 3.31 | 8.81 | 8.42 | 4.53 | 4.42 | 11.7 | 11.1 | |
AMDP-4 | pre-lyo | 1.18 (±0.03) | 1.16 (±0.05) | 3.33 (±0.10) | 3.36 (±0.11) | 9.19 (±0.44) | 9.46 (±0.46) | 4.73 (±0.18) | 4.76 (±0.13) | - 3 | - 3 |
post-lyo | - 2 | 1.12 (±0.07) | - 2 | 3.21 (±0.15) | - 2 | 9.16 (±0.79) | - 2 | 4.49 (±0.31) | - 2,3 | 11.2 (±0.3) |
Manufacturing Process | N |
---|---|
AMDP-1 | 8 |
AMDP-2 | 6 |
AMDP-3 | 7 |
AMDP-4 | 4 |
Manufacturing Process | Timepoint [months] | D[4;3] [µm] | Viscosity [mPa·s] | ||
---|---|---|---|---|---|
R | H | R | H | ||
AMDP-1 | 0 | 4.67 | 4.19 | 14.9 | 13.2 |
3 | 5.09 | 4.45 | 21.7 | 18.6 | |
AMDP-2 | 0 | - 1 | 4.33 | - 1 | 11.7 |
3 | - 1 | 4.85 | - 1 | 12.1 | |
AMDP-3 | 0 | 4.53 | 4.42 | 11.7 | 11.1 |
3 | 4.75 | 4.43 | 13.7 | 12.3 | |
AMDP-4 | 0 | - 1 | 3.89 | - 1 | 10.7 |
3 | - 1 | 3.79 | - 1 | 11.3 |
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Pietrzak, T.; Szendzielorz, Z.; Borychowska, J.; Ratajczak, T.; Kubisiak, M. The Impact of a Manufacturing Process on the Stability of Microcrystalline Long-Acting Injections: A Case Study on Aripiprazole Monohydrate. Pharmaceutics 2025, 17, 735. https://doi.org/10.3390/pharmaceutics17060735
Pietrzak T, Szendzielorz Z, Borychowska J, Ratajczak T, Kubisiak M. The Impact of a Manufacturing Process on the Stability of Microcrystalline Long-Acting Injections: A Case Study on Aripiprazole Monohydrate. Pharmaceutics. 2025; 17(6):735. https://doi.org/10.3390/pharmaceutics17060735
Chicago/Turabian StylePietrzak, Tomasz, Ziemowit Szendzielorz, Joanna Borychowska, Tomasz Ratajczak, and Marcin Kubisiak. 2025. "The Impact of a Manufacturing Process on the Stability of Microcrystalline Long-Acting Injections: A Case Study on Aripiprazole Monohydrate" Pharmaceutics 17, no. 6: 735. https://doi.org/10.3390/pharmaceutics17060735
APA StylePietrzak, T., Szendzielorz, Z., Borychowska, J., Ratajczak, T., & Kubisiak, M. (2025). The Impact of a Manufacturing Process on the Stability of Microcrystalline Long-Acting Injections: A Case Study on Aripiprazole Monohydrate. Pharmaceutics, 17(6), 735. https://doi.org/10.3390/pharmaceutics17060735