Investigation and rank-ordering of hydroxypropyl methylcellulose (HPMC) properties impacting controlled release performance (Part 2) – Exploring variation of HP substitution over broader range

Abstract

Hydroxypropyl methylcellulose (HPMC) is commonly used to enable controlled release (CR) of an active pharmaceutical ingredient (API) from a hydrophilic matrix tablet. In the previous study, twenty commercial batches of HPMC 2208 (METHOCEL™ K4M) were investigated, and their functionality-related characteristics (FRCs) were rank ordered by their impacts on performance. HP substitution and 2% viscosity most impacted controlled release of paracetamol from the matrix tablet model formulation. Additionally, powder dissolution temperature (PDT) was introduced as a new characterization technique to predict CR performance.

In this second part of the study, the design space was expanded via nine pilot plant HPMC prototype materials covering a broader range of HP content than that typically produced in the commercial manufacturing facility. The impact of controlled variation of HP content on rheological as well as controlled release performance from a paracetamol matrix tablet model formulation is subject of the current paper.

Increasing HP content increased API release significantly in the latter phase of controlled release (22 h). Furthermore, a three-way correlation between paracetamol release at 22 h, the broader HP substitution range, and PDT was confirmed. Based on learnings from this broader dataset, PDT has potential as an effective research tool to predict controlled release imparted by HPMC.

Introduction

Quality-by-Design (QbD) initiatives have prompted formulators to proactively characterize and account for active pharmaceutical ingredient (API), excipient and manufacturing process variabilities impacting dosage form quality and performance [[1], [2], [3], [4]]. Functionality-related characteristics (FRCs) are attributes impacting one or more functions of an excipient [5]. In other words, FRCs are excipient attributes, which could affect manufacturability and performance of the final preparation [6].

Hydroxypropyl methylcellulose (HPMC), or hypromellose, is commonly utilized as a functional excipient to impart controlled release from a hydrophilic matrix tablet. Hypromellose FRCs are particle morphology, powder flowability, molecular weight (typically characterized as viscosity of a 2% aqueous solution at 20 °C) and methoxyl (Me) and hydroxypropoxyl (HP) substitution [5]. In our previous study [7], 20 commercial batches of HPMC 2208 (METHOCEL™ K4M) were investigated in a paracetamol matrix tablet model formulation, and hypromellose FRCs were rank-ordered regarding impact on controlled release performance. HP substitution and 2% viscosity impacted controlled release of paracetamol, with HP substitution in particular being a key FRC impacting performance for the 20 commercial HPMC 2208 (METHOCEL™ K4M) batches investigated. HP substitution of these commercial HPMC 2208 (METHOCEL™ K4M) batches ranged from 7.9 to 9.1%, which represents a narrow portion of the compendial range for HPMC 2208 (4.0–12.0%). Huettermann & Feldmann [8] demonstrated significant impact of three HP substitution levels for each molecular weight grade of HPMC 2208 (METHOCEL™ K100 & K4M) on controlled release performance from a gliclazide matrix tablet model formulation, but they attained controlled release only over a 12 h duration.

In the current study the impact of HP substitution on HPMC hydrophilicity and controlled release performance from a paracetamol matrix tablet model formulation could be further highlighted via nine HPMC prototypes produced at pilot plant scale, exhibiting variation of HP substitution over a broader range from 6 to 11.4%, yet remaining within a narrow range of 2% viscosity. This was a broader substitution range that what is typically produced in the commercial manufacturing facility. Additionally, pilot plant HPMC 2208 prototypes were formulated into a second matrix tablet model formulation containing gliclazide, as practically insoluble API, and controlled release performance modulation was demonstrated over 24 h duration. The breadth of controlled release performance that was attainable across these two matrix tablet model formulations demonstrated the strong impact HP substitution had on release performance of the two API’s.

Controlled release performance from a hydrophilic matrix tablet is mainly driven by formation of a swollen HPMC hydrogel layer around the matrix tablet. This matrix tablet hydrogel must readily form at body temperature, i.e. 37 °C, in order to impart controlled release performance. The discrepancy between the well-known sol – gel transition of hydrated MC and HPMC in solution with increasing temperature and hydrogel formation from dry state for subsequent CR performance was published by Knarr & Rogers [9], and powder dissolution temperature (PDT) was introduced as a method to differentiate between the various MC and HPMC chemistries, according to the ability to hydrate in water as a function of temperature. Incorporating the pilot plant prototypes amplified the impact that HP substitution has on PDT beyond what was already observed in part 1 [7]. I.e., PDT significantly increased with increasing HP content using these pilot plant prototypes, covering a range of 42–58 °C, whereas weaker impact on precipitation and gelation temperatures from the HPMC aqueous solutions were observed. Including pilot plant HPMC 2208 prototypes in both the paracetamol and gliclazide matrix tablet model formulations affirmed the strong correlations between HP substitution, PDT, and controlled release performance.

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Materials

Paracetamol was obtained from Spectrum Chemical Mfg. Corp., USA; gliclazide was obtained from LGM Pharma, USA; and lactose (FlowLac 100) was obtained from Meggle Pharma GmbH, Germany. Talc and magnesium stearate were obtained from AppliChem GmbH, Germany and Spectrum Chemical. Building upon the twenty commercial hypromellose 2208 (METHOCEL™ K4M) materials from part 1 [7], samples from one additional commercial METHOCEL™ K4M batch and nine pilot plant prototype HPMC 2208 materials were investigated. All ingredients were of highest purity available.

Matthias Knarr, True L. Rogers, Oliver Petermann, Roland Adden, Investigation and rank-ordering of hydroxypropyl methylcellulose (HPMC) properties impacting controlled release performance (Part 2) – Exploring variation of HP substitution over broader range, Journal of Drug Delivery Science and Technology, Volume 114, Part B, 2025, 107441, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2025.107441.

Read also Part 1:

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