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Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization
Khadijah Edueng1, Denny Mahlin2, Per Larsson2
1Department of Pharmacy, Uppsala University, Uppsala Biomedical Centre, P.O Box 580, SE-75123 Uppsala, Sweden; Kulliyyah of Pharmacy, International Islamic University Malaysia, Jalan Istana, 25200 Bandar Indera Mahkota, Kuantan, Pahang, Malaysia.
Summary
A new protocol using DSC, DVS, PLM, and μDISS Profiler helps stabilize amorphous drugs. It found solution-mediated crystallization for most drugs, but solid-to-solid for glipizide, requiring specific stabilization strategies.
Area of Science:
- Pharmaceutical Sciences
- Materials Science
- Physical Chemistry
Background:
- Amorphous solid dispersions (ASDs) enhance drug solubility and bioavailability.
- Understanding crystallization mechanisms is crucial for stabilizing amorphous drugs.
- Predicting and preventing drug crystallization upon dissolution remains a challenge.
Purpose of the Study:
- To develop and apply a comprehensive experimental protocol to elucidate drug crystallization mechanisms.
- To investigate the stabilization of amorphous drug formulations using polymers.
- To identify strategies for preventing crystallization of amorphous drugs during dissolution.
Main Methods:
- Differential Scanning Calorimetry (DSC), Dynamic Vapour Sorption (DVS), Polarized Light Microscopy (PLM), and a μDISS Profiler were employed.
- Amorphous drugs (indapamide, metolazone, glibenclamide, glipizide) were formulated with polymers (HPMC, PVP).
- Crystallization mechanisms and stabilization effects were analyzed using spectroscopic and simulation techniques.
Main Results:
- Indapamide, metolazone, and glibenclamide showed solution-mediated crystallization; glipizide exhibited solid-to-solid crystallization.
- HPMC effectively prevented crystallization for indapamide and metolazone, and reduced it for glibenclamide.
- A 50:50 glipizide:PVP K30 ASD reduced but did not eliminate solid-to-solid crystallization, though dissolution was enhanced.
Conclusions:
- The developed protocol effectively differentiates crystallization mechanisms (solution-mediated vs. solid-to-solid).
- Polymer selection and formulation strategies are critical for stabilizing amorphous drugs.
- Hydrogen bonding interactions between drugs and polymers influence stabilization efficacy.