Amorphous is not always better-A dissolution study on solid state forms of carbamazepine.

Area of Science:

• Pharmaceutical Sciences
• Materials Science

Background:

• Poor aqueous solubility is a significant challenge in developing new drug candidates.
• High-energy solid-state forms, including metastable polymorphs, amorphous drugs, and polymer-based glass solutions, are strategies to enhance solubility.
• Carbamazepine serves as a model drug to investigate dissolution behavior of various solid forms.

Purpose of the Study:

• To evaluate the dissolution properties of different solid-state forms of carbamazepine.
• To assess the impact of polymers, specifically polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC), on carbamazepine dissolution.
• To compare the dissolution of crystalline carbamazepine, amorphous carbamazepine, and carbamazepine-polymer glass solutions in biorelevant media.

Main Methods:

• Dissolution testing of carbamazepine in crystalline and amorphous forms, with and without PVP or HPMC.
• Preparation and dissolution testing of carbamazepine-polymer glass solutions at various drug-to-polymer ratios (2:1, 4:1, 10:1 w/w).
• Dissolution studies conducted sequentially in biorelevant gastric and intestinal media over 2.5 hours.

Main Results:

• Crystalline carbamazepine (Form III) dissolved to 540 μg/ml, but precipitated to 436 μg/ml due to dihydrate formation.
• Amorphous carbamazepine showed lower concentrations than crystalline form and did not achieve supersaturation, rapidly converting to the dihydrate.
• Hydroxypropylmethylcellulose (HPMC) addition to crystalline carbamazepine prevented precipitation, maintaining dissolved drug concentrations, while polyvinylpyrrolidone (PVP) showed limited benefit.

Conclusions:

• Amorphous carbamazepine and its glass solutions did not enhance dissolution compared to crystalline forms, often due to rapid conversion to the less soluble dihydrate.
• Carbamazepine-polymer glass solutions generally exhibited lower or similar dissolved drug concentrations compared to crystalline carbamazepine.
• Hydroxypropylmethylcellulose (HPMC) demonstrated potential in stabilizing dissolved carbamazepine concentrations, preventing precipitation observed with other forms and polymers.