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