Ask the formulator: How to perfect controlled release with HPMC excipients

Hydroxypropyl methylcellulose (HPMC) is one such excipient. Renowned for its ability to form hydrogels, it can be used to modulate release performance from hydrophilic matrix tablets. In this blog, we delve into the expert insights of True Rogers, Technical Fellow at Roquette Pharma Solutions, to explore how HPMC can help drug developers formulate matrix tablets to address evolving patient needs. Keep reading to explore how drug release can not only be achieved, but fine-tuned by understanding key attributes of HPMC, particle size, molecular weight, polymer level, and hydroxypropyl (HP) content.

But first, let’s explore why HPMC is a preferred excipient…
Hydrophilic matrix tablets control drug release via formation of a hydrogel or swollen layer which envelopes the matrix tablet.² When aqueous media, such as that of the gastrointestinal tract, contacts the surface of the tablet and encounters HPMC, the HPMC particles hydrate, swell, and coalesce to form a contiguous swollen hydrogel layer around the outer surface of the matrix tablet.² Once formed, this layer controls active pharmaceutical ingredient (API) release through a combined mechanism of (1) diffusion of dissolved API through the hydrogel and (2) erosion of the hydrogel (as shown in Figure 1). The ability of HPMC to form this layer around the outer surface of the tablet is therefore a fundamental first step in achieving robust controlled release performance. However, with a variety of HPMC grades available, how do formulators choose the most suitable type for desired release performance?

Figure 1: Schematic description of controlled API release via combined mechanisms of diffusion through, and erosion of, the hydrogel layer.²

Critical attributes of HPMC affecting controlled release

1. Excipient chemistry: Selecting the right HPMC grade for controlled release
   “Formulators can choose HPMC excipients with different chemistries, such as HPMC 2208 (K-chemistry), 2906 (F-chemistry) and 2910 (E-chemistry). Here, chemistry refers to the molecular structure of the polymer and the level of methyl and hydroxypropyl substitution. Among HPMC chemistries, HPMC 2208 stands out as the leading choice for controlled release. It has the ability to dissolve at least 10-15 °C above 37 °C, ensuring rapid hydration and hydrogel formation at body temperature for controlled release. In contrast, other HPMC chemistries dissolve at relatively cooler temperatures, making them less effective for forming hydrogels quickly under physiological conditions.”

2. Polymer level: Higher polymer levels lead to more robust controlled release performance
   “For a selected HPMC product, polymer level (the concentration of HPMC in the formulation) is a key factor in allowing HPMC to form the enveloping hydrogel layer. We recommend at least 30% HPMC to ensure its concentration is sufficient to allow formation of a robust, contiguous enveloping hydrogel layer.³”

3. Particle size: Smaller HPMC particle sizes result in reduced controlled release duration
   “Another key factor in attaining robust controlled release from matrix tablets is HPMC particle size. Together with polymer level, particle size affects the percolation threshold of HPMC throughout the matrix tablet, which is critical for consistent hydrogel layer formation. To create a percolating network of HPMC throughout the matrix tablet, a continuous lattice of uniformly distributed HPMC particles in sufficiently close proximity is needed for them to hydrate, coalesce, and form the hydrogel layer. As a result, different particle sizes could result in diverse controlled release outcomes.

   “Smaller HPMC particles are able to create a percolating network of HPMC throughout the matrix tablet at lower concentrations than that needed for larger HPMC particles.⁴ If formulators have APIs where attaining robust controlled drug release performance is challenging, they should opt for greater guarantee of HPMC particle size, for example with METHOCEL™ Premium CR grades. If the API is more a “forgiving” one, like metformin, grades with less guarantee on particle size, like METHOCEL™ Premium, or coarser grades, like METHOCEL™ Premium DC2 for direct compression, might be suitable formulation options.”
   

4. Viscosity (molecular weight): Higher molecular weight HPMC extends controlled release duration
   “HPMC viscosity grade plays a pivotal role in achieving controlled release too because it influences ‘turnover’ of the hydrogel layer at its outermost surface, i.e. the erosion front. The viscosity grade of HPMC is directly related to its molecular weight, which impacts polymer entanglement (and thus disentanglement) at the erosion front. The higher the molecular weight of HPMC, the slower the hydrogel turnover at the erosion front, consequently extending the duration of controlled drug release.”

5. Hydroxypropyl (HP) substitution: HP content of HPMC can impact controlled release
   “To develop even more advanced controlled release delivery systems, formulators can further fine-tune release through HP substitution. Changing the HP content of HPMC impacts its hydrophilicity and dissolution temperature, which can influence the rate of hydrogel formation at body temperature, and therefore the release of API. This next-level controlled release could be advantageous in certain therapeutic fields where precise release is necessary for safe, long-term treatment of conditions, such as epilepsy, diabetes, hypertension, and chronic pain management.^5,6

   “HP substitution could be especially beneficial for challenging APIs, like gliclazide. Gliclazide is a poorly soluble API commonly used to treat type 2 diabetes; however, administration of this API can result in hypoglycemia (low blood sugar levels) if release is not tightly controlled over a duration interval of six to eight hours. Our data reveals that matrix tablets containing HPMC with higher HP substitution deliver the desired release kinetics of this particular API over the required duration.⁷”
   

6. Beyond HPMC: Filler solubility can influence drug release rates
   “With decades of formulation expertise, we understand how every component in a matrix tablet can affect controlled release performance, from active ingredients to binders, fillers, and rate-controlling polymers. Beyond the rate-controlling polymer, filler solubility can influence drug release from the matrix tablet. Soluble fillers like mannitol and lactose promote faster release of poorly soluble APIs that depend more on erosional release, while insoluble fillers such as starch and microcrystalline cellulose impede release of more soluble APIs that depend more on diffusional release, providing additional levers for optimizing formulation performance. Our technical team can help drug developers select the optimal excipients and complementary ingredients to achieve desired quality and performance.”
   

Powder dissolution temperature: A predictive tool for controlled release performance
“As HPMC can deliver a range of performances in controlled release applications, being able to predict these performances would be an advantage for drug developers. As such, we set out to investigate whether key rheological attributes of HPMC—including powder dissolution temperature (PDT), shear rate dependent viscosity, onset gelation temperature and gelation temperature—could serve as predictive tools for controlled release performance, using HPMC 2208 (METHOCEL™ K4M) as rate-controlling polymer.⁸

“Our investigation revealed strong correlation between PDT—the temperature at which a powdered material begins to dissolve in a liquid—and the level of HP substitution in various batches of HPMC 2208 (METHOCEL™ K4M).⁸ As HP substitution increased, PDT also increased, suggesting that higher HP substitution directly impacts HPMC hydration vs. temperature.⁸ These findings suggest that PDT could possibly be used as a rapid screening tool to approximate how a particular HPMC material might modulate API release from a matrix tablet. However, further investigation is needed to determine the strength of this correlation.”

Master controlled release with METHOCEL™ HPMC excipients
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1. Ghormade, J.M, Yadav, S.K, et al. (2023) The role of matrix tablet in controlled release drug delivery system. GSC Biological and Pharmaceutical Sciences: 23(01), 220–225.
2. Colombo P, Bettini R, Santi P, Peppas NA. (2000)Swellable matrices for controlled drug delivery: gel-layer behaviour, mechanisms and optimal performance. Pharm Sci Technolo Today: 3: 198–204.
3. Aguilar-de-LeyvaCelia et al. (2012) European Journal of Pharmaceutics and Biopharmaceutics: 80: 136-142.
4. Proprietary technical data. IFF Pharma Solutions, unpublished (2020).
5. Wheless JW, Phelps SJ. (2018) A Clinician's Guide to Oral Extended-Release Drug Delivery Systems in Epilepsy. J Pediatr Pharmacol Ther: 23(4):277-292.
6. Han KA, Lee YH, Son HS, Song KH, Kim SY, Chung CH, Jang HC, Lee KW, Cha BY, Song KH, Ko YK, Lee PB, Kim BJ, Kim S, An T, Kim YC. (2022) Efficacy and Safety of a New Sustained-release Pregabalin Formulation Compared With Immediate-release Pregabalin in Patients With Peripheral Neuropathic Pain: A Randomized Noninferiority Phase 3 Trial. Clin J Pain: 28;38(5):343-350.
7. Proprietary technical data. IFF Pharma Solutions, unpublished (2020).
8. Knarr M, Rogers TL, Petermann O, Adden R. (2024) Investigation and rank-ordering of hydroxypropyl methylcellulose (HPMC) properties impacting controlled release performance. Journal of Drug Delivery Science and Technology. 104:106425