(W1130-01-04) Predicting Hydroxypropyl Methylcellulose-Controlled Release Matrix Performance with Powder Dissolution Temperature

Purpose: Use rheological tests to investigate mismatch between gel formation and controlled-release (CR) performance, and analyze hydroxypropyl methylcellulose properties to determine which factors most strongly influence CR performance. Matrix tablets are one of the most convenient and relatively inexpensive means to modulate release of active pharmaceutical ingredients (APIs) with a wide range of solubility and dosage strength [1]. Hydroxypropyl methylcellulose (HPMC) is the excipient of choice for hydrophilic matrix tablet formulations [2]. Hydrophilic matrix tablets control the release of APIs through formation of a swollen layer [3]. This layer forms when liquid contacts the tablet surface and encounters the HPMC. The HPMC particles, which are uniformly distributed throughout the matrix tablet, hydrate, swell, and coalesce. This creates a contiguous swollen layer around the core of the tablet. Controlled release occurs via a combination of dissolved API diffusion through the layer and erosion of the outermost swollen surface, called the erosion front. At first glance, one might think that gelation properties of the polymeric excipient would justify how it imparts CR performance. Gelation is not the sole factor. Methylcellulose (MC) solutions, when heated, make stronger gels than HPMC solutions under similar conditions [4]; yet HPMC outperforms MC in CR performance from matrices [6]. Gel strength in the dissolved state is therefore not solely predictive of CR performance. This study aimed to identify properties, like powder dissolution temperature (PDT), of cellulose ethers, like MC and HPMC, that better predict CR performance. PDT describes the onset of hydration of dispersed polymeric particles in medium as a function of temperature.

Methods: Rheological temperature sweeps were performed in oscillation mode at 1 °C/min heating rate under constant frequency and deformation of 2 Hz and 2%, respectively. Multiple grades of HPMC (METHOCEL™ K4M, E4M, and F4M) and MC (METHOCEL™ A4M & A16M SG) were dissolved at 2% concentration. The PDTs of the three grades of HPMC and two grades of MC were measured using a cup and stirrer rheometer setup. Each powdered material was suspended in hot water. The suspension was then cooled at 1 °C per minute, and the rheometer recorded torque increase with decreasing temperature. METHOCEL™ K4M HPMC commercial and prototypes, with controlled hydroxypropyl differences, were then formulated into matrix tablets containing HPMC 30% (w/w), paracetamol 50%, lactose 18%, magnesium stearate 1%, and talc 1%. Dissolution was conducted in pH 5.7 phosphate buffer with USP 2 paddle speed set to 50 rpm.

Results: Oscillatory rheological temperature sweep measurements differentiated between gelation and precipitation. Elastic properties, i.e. storage modulus G’, changed as solution temperature increased. The decreases and increases in G’ showed temperatures at which the polymer underwent precipitation and gelation, respectively. This test confirmed the MC grades formed strong gels (Figure 1). The storage modulus G’ numbers for both MC grades rose quickly around 50-60 °C and plateaued at a high level. In contrast, the HPMC grades precipitated at 60 °C and above, as shown by decreasing G’, before forming weak gels as the temperature rise continued. Regarding PDT  (Figure 2), METHOCEL™ K-Chemistry HPMC had the highest PDT of >50 °C, followed by E and F-Chemistries. The METHOCEL™ A-Chemistry products had notably lower PDTs, in the range of ≤30 °C and therefore are not suitable for CR performance as shown in earlier studies [6]. The 30 °C PDT recorded for METHOCEL™ A4M is below body temperature. As such, the material will not hydrate and form the enveloping swollen layer upon administration. Without swollen layer formation, MC would not control API release from the tablet. This explains why METHOCEL™ K-Chemistry HPMCs are broadly used in CR matrices. Further investigation showed direct correlation between hydroxypropyl (HP) content in the polymer and PDT. PDT increased from about 40 to 55 °C when HP content was increased from about 6 to 11%. These two properties also directly correlated with matrix tablet CR performance: Paracetamol release at 22 h increased from about 80 to 90% when HP content was increased from about 6% to 11%.

Conclusion: PDT is a better rheological predictor of MR performance than solution gelation strength. The HP content of HPMC polymers is directly correlated with the polymers’ corresponding PDT and CR performance.

References: 1. Fuertes I, Caraballo I, Miranda A, Millán M. Study of critical points of drugs with different solubilities in hydrophilic matrices. Int J Pharm. 2010;383: 138–146.
2. Hogan JE. Hydroxypropylmethylcellulose sustained release technology. Drug Dev Ind Pharm. 1989;15: 975–999. 
3. Colombo P, Bettini R, Santi P, Peppas NA. Swellable matrices for controlled drug delivery: gel-layer behaviour, mechanisms and optimal performance. Pharm Sci Technolo Today. 2000;3: 198–204.
4. Sarkar N. Kinetics of thermal gelation of methylcellulose and hydroxypropylmethylcellulose in aqueous solutions. Carbohydr Polym. 1995;26: 195–203.
5. Velasco, M.V., J.L. Ford, A.R. Rajabi-Siahboomi, Effect of media on the dissolution profiles of propranolol hydrochloride from matrixes containing different substitution types of Methocel. Pharm. Pharmacol. Commun., 1998. 4(8):  377-383.


Figure 1: Differentiation of gelation and precipitation of MC vs. HPMC solutions


Figure 2: Comparison of the powder dissolution temperature (PDT) measurements of different MC and HPMC grades.


Figure 6: Comparison of the powder dissolution temperature (PDT) and % API release after 22 hours vs. the HP content + viscosity as well as the PDT of METHOCEL™ K4M HPMC commercial products and R&D prototypes.