Organic Solution Advanced Spray-Dried Microparticulate/Nanoparticulate Dry Powders of Lactomorphin for Respiratory Delivery: Physicochemical Characterization, In Vitro Aerosol Dispersion, and Cellular Studies
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Methods
2.2.1. Preparation of SD and co-SD Particles by Organic Solution Advanced Spray Drying in Closed Mode
2.2.2. Scanning Electron Microscopy (SEM)
2.2.3. Particle Sizing and Size Distribution
2.2.4. X-ray Powder Diffraction (XRPD)
2.2.5. Differential Scanning Calorimetry (DSC)
2.2.6. Hot Stage Microscopy (HSM) under Cross-Polarizers
2.2.7. Karl Fisher Titration (KFT)
2.2.8. Confocal Raman Spectroscopy (CRM)
2.2.9. Attenuated Total Reflectance-Fourier-Transform Infrared (ATR-FTIR)
2.2.10. In Vitro Aerosol Dispersion Performance
2.2.11. Solubility Studies
2.2.12. Partitioning Studies
2.2.13. HPLC Analysis for Solubility and LogP Experiments
2.2.14. Thermal Degradation Study of Lactomorphin
2.2.15. In Vitro Cell Culture Assays and Cell Viability Experiments after Treated with Lactomorphin
2.2.16. Computational Predictions of Physicochemical Parameters (PCP) of Lactomorphin
3. Results
3.1. Scanning Electron Microscopy (SEM)
3.2. Particle Sizing and Size Distribution by Image Analysis of SEM Micrographs
3.3. X-ray Powder Diffraction (XRPD)
3.4. Differential Scanning Calorimetry (DSC)
3.5. HSM under Cross-Polarizer Lens
3.6. Karl Fisher Titration (KFT)
3.7. ATR-FTIR Spectroscopy
3.8. Confocal Raman Microspectroscopy (CRM)
3.9. In Vitro Aerosol Dispersion Performance
3.10. Chromatography
3.11. Solubility
3.12. Partitioning Study (LogP)
3.13. Thermal Degradation Study
3.14. In Vitro Cell Culture, Development of Cell Monolayer and Cell Viability Test
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Formulations (Powder Composition = Molar Ratio) | Solvent | Outlet Temperature (°C) | Pump Rate (%) |
---|---|---|---|
SD-Lactomorphin | Methanol | - | High (100%) * |
SD-Lactomorphin | Methanol | 31 | High (75%) |
SD-Lactomorphin | Methanol | 47 | Med (50%) |
SD-Lactomorphin | Methanol | 76 | Low (25%) |
SD-Lactomorphin | Ethanol | 52 | Low (25%) |
SD-Lactomorphin | Isopropanol | 51 | Low (25%) |
co-SD-Lactomorphin:Trehalose = 75:25 | Methanol | 52 | Low (25%) |
co-SD-Lactomorphin:Trehalose = 50:50 | Methanol | 50 | Low (25%) |
co-SD-Lactomorphin:Trehalose = 25:75 | Methanol | 44 | Low (25%) |
SD-Trehalose | Methanol | 48 | Low (25%) |
Powder Composition (Molar Ratio) | Spray Drying Pump Rate (%) | Solvent | Mean Size (μm) | Size Range (μm) |
---|---|---|---|---|
Raw Lactomorphin | NA | NA | 1.51 ± 0.71 | 0.07–3.54 |
Raw Trehalose ⁑ | NA | NA | NA | NA |
SD-Trehalose | Low (25%) | Methanol | 0.95 ± 0.28 | 0.49–1.80 |
SD-Lactomorphin | Low (25%) | Methanol | 0.80 ± 0.25 | 0.21–1.60 |
Co-SD-Lactomorphin:Trehalose 25: 75 | Low (25%) | Methanol | 1.37 ± 0.56 | 0.11–3.42 |
Co-SD-Lactomorphin:Trehalose 50: 50 | Low (25%) | Methanol | 1.33 ± 0.54 | 0.43–3.86 |
Co-SD-Lactomorphin:Trehalose 75: 25 | Low (25%) | Methanol | 1.43 ± 0.37 | 0.55–2.37 |
SD-Lactomorphin * | Low (50%) | Methanol | NA | NA |
SD-Lactomorphin ⁑ | Low (75%) | Methanol | NA | NA |
SD-Lactomorphin * | Low (25%) | Ethanol | NA | NA |
SD-Lactomorphin * | Low (25%) | Isopropanol | NA | NA |
Sample/Parameter | Raw Lactomorphin | SD-Lactomorphin 75% PR | SD-Lactomorphin 50% PR | SD-Lactomorphin 25% PR | SD-Lactomorphin in EtOH | SD-Lactomorphin in Isop | Raw Trehalose | SD-Trehalose | co-SD-Lactomorphin-Trehalose (25–75) | co-SD-Lactomorphin-Trehalose (50–50) | co-SD-Lactomorphin-Trehalose (75–25) |
---|---|---|---|---|---|---|---|---|---|---|---|
Tg onset (°C) | 82.07 ± 1.53 | 82.59 ± 1.25 | 87.03 ± 0.64 | 91.30 ± 2.25 | - | 98.13 ± 9.84 | - | 50.88 ± 5.49 | 70.70 ± 1.35 | 73.62 ± 6.31 | 77.43 ±5.27 |
Tg mid (°C) | 84.69 ± 0.72 | 87.18 ± 1.47 | 90.20 ± 4.36 | 93.68 ± 0.95 | - | 100.52 ± 9.50 | - | 53.14 ± 3.89 | 73.05 ± 0.63 | 78.29 ± 6.85 | 82.13 ± 6.21 |
Tg End (°C) | 87.31 ± 0.09 | 89.99 ± 0.62 | 93.46 ± 0.61 | 96.06 ± 2.02 | - | 104.13 ± 11.62 | - | 56.27 ± 1.63 | 79.84 ± 0.71 | 82.92 ± 7.72 | 85.92 ± 7.73 |
∆Cp J/(g·°C) | 0.80 ± 0.22 | 0.72 ± 0.23 | 0.70 ± 0.0918 | 0.80 ± 0.15 | - | 1.20 ± 0.88 | - | 0.51 ± 0.01 | 0.43 ± 0.04 | 0.68 ± 0.02 | 0.66 ± 0.09 |
Endotherm1 onset (°C) | 175.72 ± 5.98 | 170.88 ± 3.63 | 177.66 ± 5.31 | 180.90 ± 0.44 | 182.08 ± 2.12 | 185.54 ± 1.37 | 94.70 ± 0.08 | 143.11 ± 5.78 | 167.96 ± 4.81 | 176.01 ± 1.59 | 174.00 ± 0.89 |
Endotherm1 peak (°C) | 175.96 ±6.20 | 171.50 ±3.24 | 177.71 ± 5.38 | 183.10 ± 1.24 | 182.26 ± 2.00 | 192.59 ± 8.00 | 95.85 ± 0.12 | 144.91 ± 4.91 | 173.47 ± 11.99 | 176.46 ± 1.74 | 174.39 ± 0.95 |
∆H1 (Enthalpy) J/g | 55.43 ± 12.35 | 43.26 ± 10.80 | 40.91 ± 2.61 | 37.25 ± 3.33 | 2.88 ± 0.52 | 13.79 ± 0.95 | 91.92 ± 7.79 | 1.34 ± 0.10 | 29.92 ± 8.67 | 3.68 ± 1.04 | 3.20 ± 0.43 |
Endotherm2 onset (°C) | - | - | - | - | 233.96 ± 22.56 | 238.41 ± 17.99 | 141.32 ± 1.20 | 187.89 ± 2.16 | 209.6 5± 8.03 | 208.65 ± 15.48 | 214.66 ± 13.72 |
Endotherm2 peak (°C) | - | - | - | - | 247.19 ± 2.1 | 243.47 ± 14.33 | 141.01 ± 1.14 | 196.89 ± 2.70 | 213.28 ± 7.12 | 210.53 ± 14.30 | 215.33 ± 14.78 |
∆H2 (Enthalpy) J/g | - | - | - | - | 35.7 ± 7.08 | 31.57 ± 4.73 | 106.90 ± 6.15 | 56.07 ± 6.21 | 34.02 ± 9.16 | 47.73 ±10.30 | 39.66 ± 8.07 |
Endotherm3 onset (°C) | - | - | - | - | - | - | 196.54 ± 1.10 | - | - | - | - |
Endotherm3 peak (°C) | - | - | - | - | - | - | 204.24 ± 1.10 | - | - | - | - |
∆H3 (Enthalpy) J/g | - | - | - | - | - | - | 118.33 ± 4.17 | - | - | - | - |
Exotherm (TC) °C | - | - | - | - | 150.58 ± 2.28 | 166.23 ± 0.46 | - | 110.01 ± 0.95 | - | - | - |
System | Water % (w/w) |
---|---|
Raw Lactomorphin | 6.07 ± 0.67 |
Raw Trehalose | 8.11 ± 1.96 |
SD-Trehalose in methanol at 25% PR | 4.76 ± 0.54 |
SD-Lactomorphin in methanol at 25% PR | 3.38 ± 0.23 |
SD-Lactomorphin in methanol at 50% PR | 3.96 ± 0.26 |
SD-Lactomorphin in methanol at 75% PR | 4.63 ± 0.70 |
SD-Trehalose in ethanol at 25% PR | 9.67 ± 0.71 |
SD-Trehalose in isopropanol at 25% PR | 4.22 ± 0.15 |
Co-SD-Lactomorphin:Trehalose 25:75 in methanol at 25% PR | 4.35 ± 0.56 |
Co-SD-Lactomorphin:Trehalose 50:50 in methanol at 25% PR | 5.04 ± 1.05 |
Co-SD-Lactomorphin:Trehalose 75:25 in methanol at 25% PR | 5.59 ± 0.38 |
Powder Formulation Composition | Emitted Dose | Fine Particle Fraction | Respirable Fraction | MMAD | GSD |
---|---|---|---|---|---|
(Molar Ratio) | (ED) (%) | (FPF) (%) | (RF) (%) | (μm) | |
Raw Lactomorphin | 100.33 ± 2.12 | 27.86 ± 0.94 | 81.06 ± 0.57 | 4.29 ± 0.24 | 4.05 ± 0.74 |
SD-Trehalose in methanol at 25% PR | 88.19 ± 0.40 | 52.00 ± 0.65 | 99.05 ± 0.20 | 1.74 ± 0.04 | 1.83 ± 0.06 |
SD-Lactomorphin in methanol at 50% PR | 88.98 ± 1.73 | 52.45 ± 7.47 | 97.70 ± 0.43 | 1.66 ± 0.02 | 1.85 ± 0.10 |
SD-Lactomorphin in methanol at 75% PR | 94.63 ± 0.78 | 46.15 ± 3.20 | 94.47 ± 3.62 | 2.16 ± 0.12 | 2.02 ± 0.01 |
SD-Trehalose in ethanol at 25% PR | 97.87 ± 15 | 63.09 ± 2.34 | 98.76 ± 0.09 | 1.98 ± 0.07 | 3.04 ± 0.09 |
SD-Trehalose in isopropanol at 25% PR | 102.29 ± 5.88 | 66.21 ± 5.17 | 98.64 ± 0.90 | 1.64 ± 0.29 | 3.01 ± 0.27 |
Co-SD-Lactomorphin:Trehalose 25:75 in methanol at 25% PR | 91.24 ± 2.26 | 50.59 ± 3.88 | 98.68 ± 0.00 | 2.21 ± 0.23 | 2.93 ± 0.96 |
Co-SD Lactomorphin:Trehalose 50:50 in methanol at 25% PR | 88.86 ± 1.13 | 53.07 ± 2.35 | 99.15 ± 0.50 | 1.89 ± 0.04 | 2.31 ± 0.00 |
Co-SD Lactomorphin:Trehalose 75:25 in methanol at 25% PR | 89.00 ± 0.67 | 45.92 ± 5.53 | 95.33 ± 3.99 | 2.07 ± 0.07 | 1.84 ± 0.17 |
pH | Major Protomer% | Minor-1 Protomer% | Minor-2 Protomer% |
---|---|---|---|
7.0 | 60.4 | 39.3 | - |
7.5 | 66.1 | 33.0 | - |
8.0 | 83.4 | 14.3 | - |
8.5 | 87.0 | 7.0 | 6.0 |
9.0 | 77.3 | 29.4 | - |
Solubility in: | pH Value | Solubility in mg/mL ± Std dev | Solubility (USP) Definition | Calculated Log S * | MOE Calculated h_logS |
---|---|---|---|---|---|
Water | 8.50 (adjusted) | 267.00 ± 6.00 | Freely soluble (Fs) | −0.6 | −0.6565 |
PBS | 8.50 (adjusted) | 570.33 ± 2.00 | Freely soluble (Fs) | −0.3 | - |
NS | 8.50 (adjusted) | 140.37 ± 0.32 | Freely soluble (Fs) | −0.9 | - |
Methanol | 7.27 (measured) | 45.67 ± 1.00 | Soluble (s) | −1.3 | - |
Ethanol | 7.30 (measured) | 18.00 ± 0.00 | Sparingly soluble (sps) | −1.7 | - |
Experimental LogP of Lactomorphin at Room Temperature (25 °C) and Physiological Temperature (37 °C) (Mean ± Standard Deviation, n = 3) | Computational LogP of Lactomorphin Protomers Exist at pH 8.5 and at Room Temperature (25 °C) | ||
---|---|---|---|
Temperature (°C) | LogP | Protomer | Computational LogP |
Major Protomer | −2.76 | ||
25 °C | −2.40 ± 0.00 | Minor-1 Protomer | −2.67 |
37 °C | −2.33 ± 0.02 | Minor-2 Protomer | −7.63 |
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Alabsi, W.; Al-Obeidi, F.A.; Polt, R.; Mansour, H.M. Organic Solution Advanced Spray-Dried Microparticulate/Nanoparticulate Dry Powders of Lactomorphin for Respiratory Delivery: Physicochemical Characterization, In Vitro Aerosol Dispersion, and Cellular Studies. Pharmaceutics 2021, 13, 26. https://doi.org/10.3390/pharmaceutics13010026
Alabsi W, Al-Obeidi FA, Polt R, Mansour HM. Organic Solution Advanced Spray-Dried Microparticulate/Nanoparticulate Dry Powders of Lactomorphin for Respiratory Delivery: Physicochemical Characterization, In Vitro Aerosol Dispersion, and Cellular Studies. Pharmaceutics. 2021; 13(1):26. https://doi.org/10.3390/pharmaceutics13010026
Chicago/Turabian StyleAlabsi, Wafaa, Fahad A. Al-Obeidi, Robin Polt, and Heidi M. Mansour. 2021. "Organic Solution Advanced Spray-Dried Microparticulate/Nanoparticulate Dry Powders of Lactomorphin for Respiratory Delivery: Physicochemical Characterization, In Vitro Aerosol Dispersion, and Cellular Studies" Pharmaceutics 13, no. 1: 26. https://doi.org/10.3390/pharmaceutics13010026
APA StyleAlabsi, W., Al-Obeidi, F. A., Polt, R., & Mansour, H. M. (2021). Organic Solution Advanced Spray-Dried Microparticulate/Nanoparticulate Dry Powders of Lactomorphin for Respiratory Delivery: Physicochemical Characterization, In Vitro Aerosol Dispersion, and Cellular Studies. Pharmaceutics, 13(1), 26. https://doi.org/10.3390/pharmaceutics13010026