(M0930-12-72) Co-processed Hydroxypropyl Methylcellulose–Mannitol as a Directly Compressible Excipient for Controlled Release

Purpose: Controlled release dosage forms deliver an effective dose of the active pharmaceutical ingredient over a prolonged duration, which is particularly advantageous to maintain a constant plasma drug concentration within the therapeutic window. This effectively overcomes the negative peak-trough effects associated with multiple dosing of immediate release formulations. In addition, controlled release formulations also feature significantly in patient-centric pharmaceutical design, given the reduced administration frequency hence improved patient compliance. The most common strategy involves dispersing the active ingredient homogeneously in a hydrophilic polymer matrix, which hydrates and swells upon contact with biological fluids to form a viscous gel to limit drug release via diffusion. Hydroxypropyl methylcellulose (HPMC) is among the most widely used excipients as a water-soluble, hydrophilic controlled release matrix. However, standard HPMC powders are associated with flow issues due to their fibrous nature, rendering it unsuitable for tableting via direct compression. In this work, HPMC co-processed with mannitol, PEARLITOL® CR H from Roquette America, Inc. (Geneva, IL) was evaluated against critical quality attributes required for a directly compressible, controlled release excipient. In addition to texturization, mannitol also acts to modulate drug release from the polymer matrix.

Methods: Co-processed HPMC-mannitol was produced by spraying mannitol solution onto fluidized HPMC particles¹ in a pilot-scale granulator (ProCell Labsystem equipped with AGT insert by Glatt). Particle morphology was assessed via scanning electron microscopy of powder samples sputter-coated with platinum. Moisture content was determined by loss on drying using a moisture analyzer (Ohaus® MB 45, USA). The flow properties of co-processed HPMC-mannitol were characterized via angle of repose and bulk/tapped density measurements, in comparison to direct compression grade HPMC (METHOCEL™ DC2 K4M, Colorcon, USA) and physical mixtures of HPMC: mannitol. The mannitol used in the physical mixture was PEARLITOL® 100 SD from Roquette America, Inc. Tabletability was evaluated by compacting 400 mg tablets using a compaction simulator (Styl’One Evolution, Medelpharm, France) fitted with a 11.28 mm, flat-faced tooling set, under external lubrication with magnesium stearate. Drug release was evaluated with drugs across a range of solubilities, namely propranolol hydrochloride (high solubility, 50 mg/mL) and metformin (very high solubility, 300 mg/mL). The controlled release performance of drug-containing co-processed HPMC-mannitol tablets was benchmarked against corresponding commercial products. Tablet shape and drug content were matched with the marketed formulations Ciplar LA 40 mg (Cipla, India) and Glucophage XR 500 mg (Merck). Dissolution studies were conducted with USP dissolution apparatus II, using a physiologically relevant, pH transition method adapted from USP < 711 > Dissolution Method A. Alcohol dose dumping test was conducted at 0, 20 and 40 % v/v ethanol in USP simulated gastric fluid, pH 1.2 with theophylline-containing tablets. Pancreatin susceptibility test was performed with USP simulated intestinal fluid in the presence and absence of pancreatin (test versus control).

Results: HPMC particles generally appeared elongated and striated when observed under scanning electron microscopy, while spray-dried mannitol comprised predominantly spherical, rough particles. Spray coating HPMC particles with mannitol solution resulted in larger, rounder particles due to deposition of mannitol on the surfaces of HPMC particles (figure 1). This was inferred to provide improved powder flowability, as characterized by angle of repose and Hausner ratio measurements (figures 2[A]) and 2[B]). The starting HPMC material recorded an angle of repose of 39.2° (fair flow by USP classification) and Hausner ratio of 1.41 (poor flow by USP classification). Compared to standard HPMC, direct compression HPMC did not demonstrate improvement in angle of repose values, and only slightly better Hausner ratio values showing poor-to-passable flow. The addition of mannitol to HPMC either by blending or co-processing, decreased angle of repose values significantly to 37.3° and 36.6°, respectively. However, a physical mixture of HPMC-mannitol did not translate to significant improvement in Hausner ratio values which corresponded to poor-to-passable flow. In contrast, co-processing HPMC with mannitol drastically reduced Hausner ratio to give good flowability. Both the physical mixture and co-processed HPMC-mannitol produced tablets of high tensile strength > 1.6 MPa at compression forces of 150 – 200 MPa which is typical for industrial production (figure 2[C]). Stronger tablets were observed for physical mixture compared to co-processed HPMC-mannitol, attributed to higher packing density of its smaller sized particles². The tablets made in-house from co-processed HPMC-mannitol exhibit a similar drug release profile when compared to the commercial products for both propranolol (Ciplar 40, Cipla) and metformin (Glucophage XR, Merck), as shown from the similarity factors (figures 3[A] and 3[B]). Co-processed HPMC-mannitol demonstrated resistance to alcohol and enzyme digestion, minimizing risk of dose dumping (figures 3[C] and 3[D]).

Conclusion: Co-processed HPMC-mannitol is an excellent candidate for a directly compressible, controlled release excipient due to improved flowability and good tabletability. The developed excipient demonstrated excellent controlled release performance for drugs over a wide range of aqueous solubilities, and good safety in the context of dose dumping risk in the presence of alcohol and enzymatic digestion.

References: 1. Boit et al. (2013), United States Patent No. US 2013/0289055 A1.
2. Kang CYX (2021). A study on site specific drug delivery.

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Figure 1. Scanning electron microscopy images of HPMC (A); spray-dried mannitol (B); physical mixture of HPMC and spray-dried mannitol (C); and co-processed HPMC-mannitol via fluid bed spray granulation (D). Scale bars represent 100 µm.



Figure 2. Flow properties of co-processed HPMC-mannitol (CP) in comparison to physical mixture (PM), HPMC and direct compression HPMC (HPMC DC): Angle of repose (A) and Hausner ratio (B). Tabletability profile of co-processed HPMC-mannitol versus physical mixture (C).



Figure 3. Drug release performance of co-processed HPMC-mannitol in comparison to commercial products for metformin HCl (A) and propranolol HCl (B). Alcohol dose dumping test (C) and pancreatin resistance test (D) with tablets containing theophylline.