Physicochemical interactions between drugs and superdisintegrants

Abstract

We have evaluated the interactions between superdisintegrants and drugs with different physicochemical characteristics, which may affect the in-vivo absorption e.g. after mucosal administration. The binding of sodium salicylate, naproxen, methyl hydroxybenzoate (methylparaben), ethyl hydroxybenzoate (ethylparaben), propyl hydroxybenzoate (propylparaben), atenolol, alprenolol, diphenhydramine, verapamil, amitriptyline and cetylpyridinium chloride monohydrate (CPC) to different superdisintegrants (sodium starch glycolate (SSG), croscarmellose sodium (CCS) and crospovidone) and one unsubstituted comparator (starch) was studied spectrophotometrically. An indication of the in-vivo effect was obtained by measuring the interactions at physiological salt concentrations. SSG was investigated more thoroughly to obtain release profiles and correlation between binding and ionic strength. The results showed that the main interactions with the anionic hydrogels formed by SSG and CCS were caused by ion exchange, whereas the neutral crospovidone exhibited lipophilic interactions with the non-ionic substances. The effect of increased ionic strength was most pronounced at low salt concentrations and the ion exchange interactions were almost completely eradicated at physiological conditions. The release profile of diphenhydramine was significantly affected by the addition of salt. It was thus concluded that the choice of buffer was of great importance for in-vitro experiments with ionic drugs. At physiological salt concentrations the interactions did not appear to be strong enough to influence the in-vivo bioavailability of any of the drug molecules.

Biopharmaceutical Understanding of Excipient Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties. Case Study: Superdisintegrants

“…The reduction in drug apparent solubility by superdisintegrant presence is more pronounced in media (compendial or biorelevant) where drugs are highly ionised (excluding the cases of increased drug solubility attributed to the change in the pH of the medium), potentially due to the presence of a high number of excipient particles on the powder surface which limits drug dissolution and/or drug solubilisation (48). For the ionic superdisintegrants (SSG, CCS), interactions between ionised drugs and the excipient polymeric chains (17,59) may also have contributed to the observed reduction in drug apparent solubility. A trend between the impact of superdisintegrants on drug apparent solubility and drug lipophilicity was not observed, apart from the case of SSG in biorelevant media, where an increase in drug solubility at 24 h was observed with increasing drug lipophilicity (when drugs are in the low ionisation state).…”

“…Electrostatic interactions between cationic drugs and the carboxyl group of SSG and CCS are known to affect the percentage of drug recovery during routine drug analysis (14,15) or delay drug release from tablet formulations (16). Drug-excipient interactions are affected by the presence of salts, as high salt concentrations suppress the binding of drugs in the hydrogels (17). Adsorption of lipophilic molecules to CPV through hydrophobic interactions has been reported (17) that could also affect drug release from pharmaceutical formulations.…”

Reversible and pH-dependent weak drug-excipient binding does not affect oral bioavailability of high dose drugs

“…Guidance on whether drug‐excipient binding interaction in an oral dosage form poses risk of low bioavailability of the drug is generally lacking in literature. Fransen et al [15] . studied the interaction between three commonly used superdisintegrants and several drugs with different physicochemical properties.…”

“…studied the interaction between three commonly used superdisintegrants and several drugs with different physicochemical properties. In addition to the ionic interactions between cationic drugs and anionic polyelectrolyte disintegrants, such as CCS and sodium starch glycollate, the authors postulated that amphiphilic drugs could interact with superdisintegrants to a greater extent than simply by ion exchange due to greater entropic gain caused by the aggregation of surfactant inside the polyelectrolyte [15] . In such cases, the interaction may not be overcome by increasing the ionic strength of the dissolution medium.…”

“…In such cases, the interaction may not be overcome by increasing the ionic strength of the dissolution medium. Nevertheless, ionic interactions could be disrupted in the presence of physiological salt concentration in the dissolution medium, which was considered as an indication of potential lack of biorelevance of such interactions [15] . Thus, the authors emphasized the importance of the strength of interaction, which was assessed by the reversibility of interaction at physiologically relevant salt concentration – a criterion that was also considered an indication of biorelevance of the interaction.…”