Two-Stage Crystallizer Design for High Loading of Poorly Water-Soluble Pharmaceuticals in Porous Silica Matrices
Abstract
:1. Introduction
2. Results
2.1. Selection of MSMPR Operating Parameters
2.2. Analysis of FEN Loading in MSMPR Experiments
2.3. Dissolution Profile Enhancement
2.4. Melting Point Depression Analysis of Nanocrystals with DSC
2.5. Crystal Form Identification with X-ray Powder Diffraction (XRPD)
2.6. Extension of Principle to Poorly Soluble Compounds
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Experimental Apparatus
4.2.1. Single-Stage MSMPR
4.2.2. Two-Stage MSMPR
4.2.3. Extension of Principle to Poorly Water-Soluble Compounds
4.3. Analytical Techniques
4.3.1. X-ray Powder Diffraction
4.3.2. Thermogravimetric Analysis
4.3.3. Differential Scanning Calorimetry
4.3.4. Solubility Measurements
4.3.5. Dissolution Testing
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Pore Size (nm) | Specific Surface Area (m2/g) | Pore Vol. (mL/g) | Theoretical Single-Stage Max. Loading from FEN Soln. (wt %) | Single-Stage Loading (wt %) | Theoretical Filled Pore Max. FEN Loading (wt %) | Two-Stage Loading (wt %) |
---|---|---|---|---|---|---|
300 | 10 | 1.0 | 37.5 | 31.4 ± 1.7 | 54.1 | 41.6 ± 1.0 |
191 | 30 | 1.5 | 47.4 | 36 ± 1.9 | 63.9 | 50.2 ± 1.8 |
151 | 31 | 1.2 | 41.9 | 36.1 ± 1.7 | 58.6 | 40.2 ± 2.5 |
105 | 52 | 1.4 | 45.7 | 36.5 ± 4.2 | 62.3 | 54.8 ± 3.7 |
53 | 94 | 1.3 | 43.8 | 39.1 ± 1.0 | 60.5 | 55.6 ± 2.2 |
38 | 138 | 1.3 | 43.8 | 40.3 ± 2.3 | 60.5 | 56.1 ± 3.5 |
35 | 300 | 1.6 | 49.0 | - | 65.4 | 56.7 ± 1.6 |
Temp. (°C) | Loading (wt %) | Notes from DSC Thermogram | |||
---|---|---|---|---|---|
Trial 1 | Trial 2 | Trial 3 | Avg. | ||
25 | 36.0 | 42.3 | 37.2 | 38.5 ± 3.5 | Single peak, confined crystals |
20 | 27.4 | 30.3 | 31.8 | 29.8 ± 2.2 | Single peak, confined crystals |
18 | 50.8 | 48.7 | 51.6 | 50.4 ± 1.5 | Single peak, confined crystals |
17 | 61.0 | 58.9 | 56.9 | 58.9 ± 2.1 | Single peak, confined crystals |
15 | 64.6 | 61.0 | 65.7 | 63.8 ± 2.5 | Two peaks, confined and surface crystals |
API | Theoret. One-Pass Max. Load from 30 mg/mL Soln. (wt %) | Theoret. Filled Pore Max. Load (wt %) | One-Pass Loading (wt %) | Two-Pass Loading (wt %) | Three-Pass Loading (wt %) |
---|---|---|---|---|---|
GSF | 4.6 | 69.1 | 3.0 ± 0.6 | 16.9 ± 1.7 | 26.1 ± 2.0 |
DSC notes | No surface crystals | No surface crystals | Some surface crystals | ||
IMC | 4.6 | 61.5 | - | 10.9 ± 2.2 | 13.2 ± 3.9 |
DSC notes | Undetected | Mostly surface crystals | Mostly surface crystals |
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Dwyer, L.; Kulkarni, S.; Ruelas, L.; Myerson, A. Two-Stage Crystallizer Design for High Loading of Poorly Water-Soluble Pharmaceuticals in Porous Silica Matrices. Crystals 2017, 7, 131. https://doi.org/10.3390/cryst7050131
Dwyer L, Kulkarni S, Ruelas L, Myerson A. Two-Stage Crystallizer Design for High Loading of Poorly Water-Soluble Pharmaceuticals in Porous Silica Matrices. Crystals. 2017; 7(5):131. https://doi.org/10.3390/cryst7050131
Chicago/Turabian StyleDwyer, Leia, Samir Kulkarni, Luzdary Ruelas, and Allan Myerson. 2017. "Two-Stage Crystallizer Design for High Loading of Poorly Water-Soluble Pharmaceuticals in Porous Silica Matrices" Crystals 7, no. 5: 131. https://doi.org/10.3390/cryst7050131