Assessing the Impact of Counterion Types on the Sustained Release Characteristics of High-Payload Drug-Ion Complex: A Case Study on Tetracycline Hydrochloride.

Abstract

Complexation of ionized hydrophilic drugs with counterions (e.g. polyelectrolytes, ionic amphiphiles, multivalent salt ions) represents a well-established formulation approach to produce sustained release of highly soluble drugs while maintaining a high drug payload. This renders the drug-ion complex an attractive alternative to the conventional polymer matrix systems. The effects of the counterion s type on the sustained release characteristics of drug-ion complexes, however, have not been investigated before under the same dissolution environment. Using antibiotic tetracycline hydrochloride (TC•HCl) as the model hydrophilic drug, we investigated the effects of three types of counterions, sodium dextran sulfate (DXT), sodium dodecyl sulfate (SDS), and K2HPO4, on (1) the sustained release characteristics, (2) long-term storage stability, (3) preparation efficiency (i.e. yield, payload), and (4) antibiotic activity of the resultant (TC•HCl)-ion complexes. The results showed that the three complexes exhibited comparable TC•HCl payloads at approximately 80% (w/w) and yield between 40-60% (w/w). They also exhibited good storage stability after 18 months and uncompromised antibiotic activity compared to the native drug. In the intestinal fluid, all three complexes could produce sustained drug release profiles, albeit at different rates ((TC•HCl)-DXT > (TC•HCl)-SDS > (TC•HCl)-HPO4), whereas in the gastric fluid, only the (TC•HCl)-DXT complex could produce a sustained release profile suitable for oral delivery. The different sustained release profiles among the complexes were attributed to their different solid forms (amorphous versus crystalline), hydrophobicity, solubility, and drug release mechanisms. The present work highlighted the importance of selecting the most suitable counterion to achieve the desired sustained drug release profile.