Long-Term Physical (In)Stability of Spray-Dried Amorphous Drugs: Relationship with Glass-Forming Ability and Physicochemical Properties
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Preparation of Samples
2.2.1. Melt-Quenching Using Differential Scanning Calorimetry
2.2.2. Spray-Drying
2.3. Physical Stability upon Storage
2.4. Solid-State Characterization
2.4.1. Powder X-ray Diffraction (PXRD)
2.4.2. Modulated Differential Scanning Calorimetry (MDSC)
Determination of Melting Point and Heat of Fusion
Solid-State Characteristics of Spray-Dried Stability Samples
Determination of GFA/GS Classes of Spray-Dried Samples
2.4.3. Raman Spectroscopy
2.4.4. Polarized Light Microscopy
2.5. Combining the PXRD, DSC, Raman Spectroscopy, and PLM Analyses
2.6. Univariate and Multivariate Analysis
3. Results and Discussion
3.1. Selection of the Dataset
3.2. Glass-Forming Ability and Glass Stability
3.2.1. Influence of Preparation Method vs. Compound GFA/GS
3.3. Long-Term Physical Stability
3.4. Relationship between GFA/GS Classifications and Storage Stability
3.5. Role of the Physicochemical Properties on the GFA and Long-Term Physical Stability
3.5.1. GFA vs. Physicochemical Properties
3.5.2. Long Term Physical Stability vs. Physicochemical Properties
3.5.3. Physicochemical Properties of Importance to GFA and Physical Stability
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Compound | GFA MQ | GFASD | MW (g/mol) | logP | HBD | HBA | RotB | PSA (Å2) | Tg MQ (°C) a | Tg SD (°C) b | Tc MQ (°C) c | Tc SD (°C) d | Tm (°C) | Trg | ΔHf (J/g) | ΔSf (Jg−1K−1) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Acetaminophen | II | I | 151 | 0.5 | 2 | 2 | 1 | 49 | 27 | n.d | 78 | n.d | 166 | 0.16 | 206 | 0.47 |
Aripiprazole | II | II | 448 | 4.6 | 1 | 4 | 7 | 45 | 37 | 31 | 91 | 63 | 136 | 0.27 | 92 | 0.22 |
Bezafibrate | III | I | 362 | 3.8 | 2 | 4 | 7 | 76 | 42 | n.d | n.d. | n.d | 182 | 0.23 | 145 | 0.32 |
Chlorpropamide | II | I | 277 | 2.3 | 2 | 3 | 4 | 84 | 19 | n.d | 62 | n.d | 127 | 0.15 | 101 | 0.25 |
Cinnarizine | II | I | 369 | 5.8 | 0 | 2 | 6 | 7 | 10 | n.d | 78 | n.d | 117 | 0.09 | 118 | 0.30 |
Clofoctol | II | I | 365 | 8.1 | 1 | 1 | 5 | 20 | −1 | n.d | 48 | n.d | 85 | −0.01 | 98 | 0.27 |
Clotrimazole | III | II | 345 | 5 | 0 | 1 | 4 | 18 | 33 | 15 | n.d. | 88 | 141 | 0.23 | 101 | 0.24 |
Droperidol | II | II | 379 | 3.5 | 1 | 4 | 6 | 53 | 36 | 33 | 117 | 73 | 149 | 0.24 | 103 | 0.24 |
d-salicin | II | I | 286 | −1.2 | 5 | 7 | 4 | 120 | 62 | n.d | 129 | n.d | 198 | 0.31 | 201 | 0.43 |
Fenofibrate | III | I | 361 | 5.2 | 0 | 4 | 7 | 53 | −16 | n.d | n.d. | n.d | 79 | −0.20 | 98 | 0.28 |
Flurbiprofen | II | I | 244 | 4.2 | 1 | 3 | 3 | 37 | −2 | n.d | 38 | n.d | 111 | −0.02 | 116 | 0.30 |
Glibenclamide | III | II | 494 | 4.8 | 3 | 5 | 8 | 122 | 61 | 75 | n.d. | 130 | 171 | 0.36 | 119 | 0.27 |
Glipizide | II | II | 446 | 1.9 | 3 | 6 | 7 | 139 | 62 | 64 | 112 | 68 | 200 | 0.31 | 208 | 0.44 |
Hydrochlorothiazide | III | II | 298 | −0.1 | 3 | 7 | 1 | 135 | 119 | 76 | n.d. | 125 | 264 | 0.45 | 122 | 0.23 |
Hydrocortisone | III | II | 362 | 1.6 | 3 | 5 | 2 | 95 | 93 | 96 | n.d. | 137 | 216 | 0.43 | 121 | 0.25 |
Ibuprofen | III | I | 206 | 3.5 | 1 | 2 | 4 | 37 | −40 | n.d | n.d. | n.d | 73 | −0.55 | 135 | 0.39 |
Indapamide | III | III | 366 | 2.9 | 2 | 5 | 3 | 101 | 107 | 106 | n.d. | n.d | 163 | 0.66 | 74 | 0.17 |
Ketoconazole | III | II | 531 | 4.3 | 0 | 6 | 7 | 69 | 48 | 43 | n.d. | 104 | 145 | 0.33 | 103 | 0.25 |
Ketoprofen | III | I | 254 | 3.1 | 1 | 3 | 4 | 54 | 0 | n.d | n.d. | n.d | 91 | −0.01 | 114 | 0.31 |
Metolazone | III | II | 366 | 4.1 | 2 | 5 | 2 | 101 | 121 | 137 | n.d. | 194 | 261 | 0.46 | 96 | 0.18 |
Prednisone | III | II | 358 | 1.5 | 2 | 5 | 2 | 92 | 137 | 96 | n.d. | 92 | 186 | 0.74 | 95 | 0.21 |
Probucol | III | II | 517 | 11.3 | 2 | 4 | 8 | 91 | 29 | 26 | n.d. | 44 | 123 | 0.24 | 68 | 0.17 |
Procaine | III | I | 236 | 1.9 | 1 | 4 | 7 | 56 | −36 | n.d | n.d | n.d | 58 | −0.62 | 110 | 0.33 |
Sulfamerazine | III | I | 264 | 0.1 | 2 | 6 | 3 | 106 | 69 | n.d | n.d. | n.d | 233 | 0.30 | 154 | 0.30 |
Sulfathiazole | III | II | 255 | 0.1 | 2 | 6 | 3 | 122 | 65 | 51 | n.d. | 71 | 197 | 0.33 | 117 | 0.25 |
Tinidazole | II | I | 247 | −0.4 | 0 | 5 | 4 | 106 | −7 | n.d | 53 | n.d | 123 | −0.06 | 145 | 0.37 |
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Edueng, K.; Bergström, C.A.S.; Gråsjö, J.; Mahlin, D. Long-Term Physical (In)Stability of Spray-Dried Amorphous Drugs: Relationship with Glass-Forming Ability and Physicochemical Properties. Pharmaceutics 2019, 11, 425. https://doi.org/10.3390/pharmaceutics11090425
Edueng K, Bergström CAS, Gråsjö J, Mahlin D. Long-Term Physical (In)Stability of Spray-Dried Amorphous Drugs: Relationship with Glass-Forming Ability and Physicochemical Properties. Pharmaceutics. 2019; 11(9):425. https://doi.org/10.3390/pharmaceutics11090425
Chicago/Turabian StyleEdueng, Khadijah, Christel A.S. Bergström, Johan Gråsjö, and Denny Mahlin. 2019. "Long-Term Physical (In)Stability of Spray-Dried Amorphous Drugs: Relationship with Glass-Forming Ability and Physicochemical Properties" Pharmaceutics 11, no. 9: 425. https://doi.org/10.3390/pharmaceutics11090425