Glass drug
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Glass Drug Formulations: Predictive Models and Stability
Predictive Models for Glass-Forming Ability in Drug Development
Early Predictions Using Molecular Weight and Thermal Properties
Research has shown that the glass-forming ability (GFA) of drug compounds can be predicted early in the drug development process using molecular weight (Mw) and thermal properties. A study involving 50 structurally diverse drug molecules found that Mw alone could correctly predict the GFA for 90% of the drugs. Specifically, drugs with Mw greater than 300 g/mole are likely to transform into an amorphous state using standard processing technologies. Additionally, the glass transition temperature and Mw were able to predict the physical stability of these glass-forming compounds upon storage with 78% accuracy.
In Silico Prediction Models
Advancements in computational tools have enabled the prediction of GFA from molecular structure alone. A novel model using partial least-squares projection to latent structure discriminant analysis (PLS-DA) and molecular descriptors was able to correctly classify 15 out of 16 compounds. This model suggests that larger molecules with fewer benzene rings, low molecular symmetry, branched carbon skeletons, and electronegative atoms are more likely to form a glass.
Manufacturing Techniques and Their Impact on Glass Solutions
Spray Drying, Melt Extrusion, and Ball Milling
The manufacturing process significantly influences the physicochemical properties of glass solutions. A study comparing spray drying, melt extrusion, and ball milling for three poorly water-soluble drugs (carbamazepine, dipyridamole, and indomethacin) found that the physical stability of the products varied, with indomethacin being the most stable. The manufacturing technique did not affect physical stability but did impact dissolution rates, with spray-dried materials generally showing poorer dissolution compared to melt-extruded and ball-milled products.
Continuous Cooling and Isothermal Transformation
Continuous-cooling-transformation (CCT) and time-temperature-transformation (TTT) diagrams have been used to predict the critical cooling rate necessary to convert drugs from melt to an amorphous form. TTT diagrams, although overestimating the actual critical cooling rate, allowed differentiation of drugs based on their GFA. Drugs were categorized into those requiring high, moderate, or low cooling rates to become amorphous.
Stability and Practical Applications
Long-Term Physical Stability
The long-term physical stability of spray-dried amorphous drugs is influenced by their GFA and physicochemical properties. A study involving 26 glass-forming drugs found that the GFA/GS classification was method-dependent, with significant differences between spray-drying and melt-quenching methods. Stability under dry conditions could be predicted from GFA/GS classification and thermal properties, but stability under humid conditions could not.
Bioactive Glass as Drug Delivery Systems
Bioactive glasses have been explored as controlled release devices for drugs like tetracycline. These glasses, when combined with beta-cyclodextrin, showed significant bacteriostatic activity and slowed drug release, enhancing the bioactivity of the glass.
Photoprotection of Liquid Formulations
Efficacy of Colored Glass
The use of colored glass, particularly red glass, has been shown to protect dihydropyridine antihypertensive drugs in liquid formulations from light-induced degradation. While transparent glass was ineffective, amber glass provided some protection, and red glass offered satisfactory photoprotection, maintaining drug concentrations above 90% after 1 hour under forced light conditions.
Conclusion
The ability to predict and enhance the glass-forming ability and stability of drug compounds is crucial in pharmaceutical development. Early predictions using molecular weight and thermal properties, combined with advanced computational models, can guide the formulation of stable amorphous drugs. Manufacturing techniques and protective packaging also play significant roles in ensuring the efficacy and stability of these formulations.
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