Microenvironmental pH and microviscosity inside pH-controlled matrix tablets: an EPR imaging study.
Incorporation of pH modifiers is a commonly used strategy to enhance the dissolution rate of weakly basic drugs from sustained release solid dosage forms. Electron paramagnetic resonance imaging (EPRI) was applied to spatially monitor pH(M) and the rotational correlation time (tau(R)), a parameter which is closely related to the surrounding microviscosity inside HPMC (hydroxypropylmethylcellulose) matrix tablets. Fumaric, citric, and succinic acid were employed as pH modifiers. 4-(methylamino)-2-ethyl-5,5-dimethyl-4-pyridine-2-yl-2,5-dihydro-1H-imidazole-1-oxyl (MEP) was used as spin label. Fumaric and citric acid reduced the pH(M) to equal extents in the initial phase. With the progress of hydration, the more soluble citric acid diffused out from the tablet resulting in an increase in pH(M), originating at the outer layers. In contrast, fumaric acid maintained a constantly reduced pH(M) inside the entire tablet. Due to its lower acidic strength, succinic acid did not reduce the pH(M) as effectively as the other pH modifiers used. The more water-soluble acids stimulated the water penetration into the matrix system, thereby rapidly decreasing tau(R). Once the matrix tablets were hydrated, the included pH modifiers influenced tau(R) insignificantly. EPRI, a novel approach for monitoring pH(M) and tau(R) non-invasively and spatially resolved, was used successfully for the optimization of an pH-controlled formulation.
Novartis Pharma AG, Technical R and D, CH-4002 Basel, Switzerland. stefanie.siepe@novartis.com
Stefanie
S
Siepe
Werner
W
Herrmann
Hans-Hubert
HH
Borchert
Barbara
B
Lueckel
Andrea
A
Kramer
Angelika
A
Ries
Robert
R
Gurny
D002626:Chemistry, Pharmaceutical; D019343:Citric Acid / Q000737:chemistry; D003692:Delayed-Action Preparations; D004176:Dipyridamole / Q000737:chemistry; D004578:Electron Spin Resonance Spectroscopy; D005650:Fumarates / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D012995:Solubility; D019802:Succinic Acid / Q000737:chemistry; D013607:Tablets; D014783:Viscosity; D014867:Water / Q000737:chemistry
D003692:Delayed-Action Preparations; D005650:Fumarates; D011108:Polymers; D013607:Tablets; D014867:Water; D019343:Citric Acid; D065347:Hypromellose Derivatives; D004176:Dipyridamole; C032005:fumaric acid; D008747:Methylcellulose; D019802:Succinic Acid