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J Pharm Sci. 2014 Mar;103(3):920-6. doi: 10.1002/jps.23852. Epub 2014 Jan 13.

Surfactant-mediated dissolution of metformin hydrochloride tablets: wetting effects versus ion pairs diffusivity.

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1
Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey, 08903-0191.

Abstract

The aqueous solubility of metformin (pKa: 2.8 and 11.5) in the pH range of 1.2-6.8 is 300 mg/mL. Thus, the dissolution of metformin hydrochloride tablets should be pH independent. However, 850 mg metformin hydrochloride tablets dissolved more slowly in pH 1.2 and 4.5 dissolution media than in pH 6.8 medium. It is hypothesized that the additional protonation of metformin at the acidic pH results in higher solvation and a larger hydrodynamic radius, leading to slower diffusion and dissolution. This hypothesis was supported by the observation that cationic metformin and anionic sodium lauryl sulfate (SLS), 0.1% (w/v), formed an insoluble salt (1:2 molar ratio) at pH 1.2 and 4.5, but not at pH 6.8. SLS at 0.01% (w/v) in all three media enhanced metformin dissolution. The slower metformin dissolution at pH 1.2 and 4.5 media with SLS can be attributed to the formation of metformin-lauryl sulfate (Met-LS) (1:2 and 1:1) ion pairs, which are more hydrophobic than Met-LS (1:1) ion pairs at pH 6.8. Slower metformin diffusivity in pH 4.5 with 0.05% (w/v) SLS was observed by diffusion-ordered spectroscopy nuclear magnetic resonance. Improved metformin wetting by SLS outweighed the lower diffusivity of metformin-LS ion pairs because similar enhancement in dissolution was noted with 0.5% (w/v) nonionic polysorbate 80.

KEYWORDS:

NMR; diffusion; dissolution; formulation; micelle; pH; precipitation; solubility; surfactants; wetting

PMID:
24549733
DOI:
10.1002/jps.23852
[Indexed for MEDLINE]
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