Investigation and rank-ordering of hydroxypropyl methylcellulose (HPMC) properties impacting controlled release performance

Hydroxypropyl methylcellulose (HPMC) is a commonly used excipient to enable controlled release (CR) performance from a hydrophilic matrix tablet. Quality-by-Design (QbD) initiatives have prompted formulators to proactively characterize and account for variabilities in process parameters and ingredient properties that could impact dosage form performance. Some excipient properties are referred to as functionality-related characteristics (FRCs), which could impact manufacturing or performance of the dosage form. HPMC FRCs include. - Particle morphology (e.g. particle size) - Methyl substitution (%Me) - Powder flowability - Hydroxypropyl substitution (%HP) - Molecular weight (characterized as viscosity) This study investigated the batch-to-batch variability of twenty HPMC 2208 (METHOCEL TM K4M) batches produced across a time period of three years and the effect of FRC variability on CR performance. The study also examined the potential of using rheological characterization as a proxy for CR performance. The key findings were: • FRC variability was very low from batch to batch, and CR performance was reproducible. • %HP substitution was found to be the most significant FRC impacting CR performance, followed by 2 % viscosity. • Particle size and %Me substitution did not significantly impact matrix tablet performance within the ranges investigated. • Paracetamol release increased with increasing %HP content, but over a relatively narrow release range. • From the studied rheological attributes the powder dissolution temperature (PDT) was found to be a promising proxy for CR performance. Further investigation is needed to determine the strength of the correlation Constant paracetamol release vs. time from the matrix tablets as a function of twenty commercial HPMC 2208 material used. • Functionality-related characteristic (FRC) variability was very low from batch to batch, leading to constant CR performance. • Hydroxypropyl substitution was found to be the most significant FRC impacting CR performance, followed by 2 % viscosity. • Particle size and methyl (% Me) substitution did not significantly impact matrix performance within the ranges investigated. • Paracetamol release increased with increasing % HP content, but over a relatively narrow release range. • From all rheological attributes, the powder dissolution temperature PDT was the most promising proxy for CR performance.