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  • Title: Improved dissolution of an enteric polymer and its amorphous solid dispersions by polymer salt formation.
    Author: Qi Q, Taylor LS.
    Journal: Int J Pharm; 2022 Jun 25; 622():121886. PubMed ID: 35661745.
    Abstract:
    Weakly acidic polymers, historically used as enteric coatings, are increasingly being employed in solubility-enhancing amorphous solid dispersion (ASD) formulations. However, there is a lack of fundamental understanding around how these carboxylic acid-containing polymers dissolve, in particular when molecularly mixed with a lipophilic drug, as in an ASD. Identification of critical factors dominating their dissolution is vital for rational design of new polymers with enhanced release properties to address contemporary ASD delivery challenges, notably achieving good release at higher drug loadings. Herein, after identification of polymer solubilization via ionization as the rate limiting step for dissolution, hydroxypropylmethyl cellulose phthalate (HP-50) was converted to a salt by neutralization of the phthalic acid groups with different bases. Surface normalized dissolution was performed to assess the dissolution rate improvement achieved by polymer pre-ionization via salt formation. Polymer salts showed ∼ 3-fold faster release than HP-50 at pH 6.8 (50 mM sodium phosphate buffer). Importantly, a polymer salt was able to maintain a rapid dissolution rate, irrespective of the buffer capacity of the medium, whereas the protonated polymer showed greatly diminished dissolution as medium buffer capacity decreased toward physiological gastrointestinal tract values. HP-50 and two polymer salts were formulated into ASDs with miconazole, a lipophilic and weakly basic antifungal drug, at a 20% drug loading. Rapid drug release rates were achieved with polymer salt ASDs, whereby drug release was 14 times faster than from the protonated HP-50 ASD. This study highlights the critical role of polymer ionization and buffer capacity in the dissolution of HP-50-based systems and how pre-ionization via polymer salt formation is a successful strategy for the design of new polymers for improved ASD performance.
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