Enhancing and Sustaining AMG 009 Dissolution from a Matrix Tablet Via Microenvironmental pH Modulation and Supersaturation

Abstract

Abstract. The objective of this study was to investigate the combined effect of pH modifiers and nucleation inhibitors on enhancing and sustaining the dissolution of AMG 009 tablet via supersaturation. Several bases and polymers were added as pH modifiers and nucleation inhibitors, respectively, to evaluate their impact on the dissolution of AMG 009 tablets. The results indicate that sodium carbonate, among the bases investigated, enhanced AMG 009 dissolution the most. HPMC E5 LV, among the nucleation inhibitors tested, was the most effective in sustaining AMG 009 supersaturation. The release of AMG 009 went from 4% for tablets which did not contain both sodium carbonate and HPMC E5 LV to 70% for the ones that did, resulting in a 17.5-fold increase in the extent of dissolution. The effect of compression force and disintegrant on the dissolution of tablets were also evaluated. The results indicate that compression force had no effect on AMG 009 release. The addition of disintegrating agents, on the other hand, decreased the dissolution of AMG 009.

Application of a Novel ‘Make and Test in Parallel’ Strategy to Investigate the Effect of Formulation on the Pharmacokinetics of GDC-0810 in Healthy Subjects

“…However, due to super-saturation, the salt may sometimes precipitate out as the insoluble free form upon dissolution, forming a layer on the surface of the dissolving salt, which may result in low bioavailability of the drug. The addition of functional excipients, such as surfactants and pH modifiers, in the dosage forms have been reported to be an effective tool in improving the dissolution behavior of compounds with pH dependent solubility ( 5 , 6 ). Further, in vitro dissolution studies have shown that incorporating 15% sodium bicarbonate (NaHCO 3 ) as an alkalizing agent in the solid dosage form of GDC-0810 can enhance its release via micro-environmental pH modulation, resulting in increased dissolution ( 7 ).…”

Enhancing and Sustaining AMG 009 Dissolution from a Bilayer Oral Solid Dosage Form via Microenvironmental pH Modulation and Supersaturation

“…In the previous studies (20), it was found that, when Na 2 CO 3 was removed from the formulation and dissolved in the dissolution medium prior to tablet dissolution study, only 4% AMG 009 was released from the matrix tablets. This indicates that the dissolution enhancement in aforementioned study is a result of microenvironmental pH modulation by Na 2 CO 3 because the pH of bulk dissolution medium is the same before and after dissolution and is not impacted by such a small amount of Na 2 CO 3 .…”

“…These facts indicate that a strong basic pH modifier, such as sodium carbonate with a pk a value of 10.3, is needed in the dosage form to increase the pH of the microenvironment and thus the solubility, resulting in increased dissolution of AMG 009. The detailed study and selection of basic pH modifiers were described in a previous publication (20). Figure 3 shows the dissolution profiles of matrix and bilayer capsules.…”

Amorphous Solid Dispersions

“…Generally, weak organic acids, such as ascorbic, adipic, citric, fumaric, glutaric, succinic, malic, tartaric acids, are used to decrease microenvironmental pH of weakly basic drugs. Various weak bases, such as sodium carbonate, sodium bicarbonate, magnesium oxide, calcium carbonate, potassium phosphate, sodium phosphate, and so forth, are used to increase the microenvironmental pH and thereby enhance the dissolution rate of poorly water-soluble weakly acidic drugs (Bi et al 2011b;Tran et al 2009. The pH modifiers may also prevent or retard conversion of salts into their unionized forms and, therefore, the dissolution rates remain high (Badawy et al 2006).…”

“…For a weakly acidic drug, AMG009 with poor intrinsic solubility (0.6 μg/mL), Bi et al (2011aBi et al ( , 2011b prepared solid dispersions by using various nucleation inhibitors, such as HPMCE5 LV, HPMC K100 LV, plasdone K-17 (PVP K17); pHmodifiers, such as sodium carbonate, sodium bicarbonate, tromethamine, sodium acetate, sodium phosphate; and sodium citrate dihydrate. Both the nucleation inhibitor and the pH modifier were necessary to increase the dissolution rate and maintain supersaturation of the drug in the dissolution media.…”