pH-Dependent supersaturation from amorphous solid dispersions of weakly basic drugs

Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers

“…70 Similarly, for clotrimazole-HPMCAS ASDs, supersaturated solutions were generated, although the lowest pH studied was pH 3. 26 In the case of DLM ASDs, the extent of drug release and supersaturation observed after 60 min depended on the medium pH. For most ASDs, the concentration after 60 min of immersion exceeded the crystalline solubility and therefore a supersaturated solution was generated in the gastric compartment (Figure 9, when the SR is >1, the solution is supersaturated), although the extent of supersaturation varied depending on the pH.…”

“…The gastric residence time also depends on the prandial state, with values typically in the range of 15−60 min for the fasted state 60,61 and 2−5 h for the fed state. [40][41][42]58 Historically, dissolution medium pH is an important variable, known to impact release from many dosage forms, in particular those containing ionizable APIs 26 or an enteric coating. 42,62,63 In addition, buffer capacity, ionic strength, and buffer type have been observed to impact drug release 64−66 as well as polymer dissolution.…”

“…Conversely, systems with strong/ extensive drug−polymer interactions will show a lower extent of release. 26 Given the low extent of release compared to ASDs with other polymers, it is inferred that HPMCP-55, which has a higher phthalyl content, higher molecular weight, and higher acid resistance than HPMCP-50, 55 may form relatively stronger/more extensive interactions with the drug, leading to reduced release at a pH where the polymer is insoluble.…”

“…24 Therefore, if a drug has a tendency to undergo crystallization when the formulation is immersed in the gastric fluid, the inhibitory properties of a polymer in this environment need to be considered. 6,26,27 In addition, it may be more challenging to inhibit the crystallization of Biopharmaceutics Classification System class II weakly basic drugs due to their pH-dependent solubility. 28−30 These compounds can undergo ionization and dissolution in acidic media but may crystallize upon transit to the higher pH environment of the small intestine.…”

Dissolution Behavior of Weakly Basic Pharmaceuticals from Amorphous Dispersions Stabilized by a Poly(dimethylaminoethyl Methacrylate) Copolymer

“…Weak bases (as well as neutral compounds) can leech from ASDs in gastric conditions at rates that exceed the dissolution of stabilizing excipients, such as the commonly employed acidic stabilizer hydroxypropyl methylcellulose acetate succinate (HPMCAS), which can result in precipitation and in vivo exposure sensitive to pH. − Although methods have been devised to mitigate high concentrations of API at low pH by dosing large particle size amorphous dispersions, , the same strategies that slow dissolution can negatively impact bioperformance . Additionally, strong hydrogen bonding between drug and polymer can reduce the maximum achievable drug concentration during dissolution. , An alternative strategy is to disperse API in readily water-soluble carriers, such as poly­(vinyl pyrrolidone- co -vinyl acetate), which ensures the presence of dissolved polymer in gastric conditions . However, there is a sensitive interplay between drug properties, polymer properties, and drug loading in amorphous dispersions that determines the dissolution rate and precipitation liability of hydrophobic compounds released from a neutral polymer. , …”