Mannitol-Coated Hydroxypropyl Methylcellulose as a Directly Compressible Controlled Release Excipient for Moisture-Sensitive Drugs
Abstract
Background/Objectives: Hydroxypropyl methylcellulose (HPMC) is one of the most commonly used hydrophilic polymers in formulations of matrix tablets for controlled release applications. However, HPMC attracts moisture and poses issues with drug stability in formulations containing moisture-sensitive drugs.
Methods: Herein, the moisture sorption behavior of excipients and drug stability using aspirin as the model drug in matrix tablets were evaluated, using HPMC and the newly developed mannitol-coated HPMC, under accelerated stability conditions (40 °C, 75% relative humidity) with open and closed dishes.
Results: Tablets prepared with mannitol-coated HPMC showed a slower drug degradation rate compared to tablets prepared with directly compressible HPMC. Initial moisture content and hygroscopicity were stronger predictors of drug stability compared to water activity when comparing samples without similar moisture content. In the early stage (day 0 to 30), the aspirin degradation rate was similar in both open and closed conditions, as moisture content is the main degradation contributor. In the later stage (day 30 to 90), aspirin degradation was faster under closed conditions than under open conditions, likely due to autocatalytic effects caused by the volatile acidic by-product entrapped in the closed environment.
Conclusions: The findings from this study reinforced the importance of judicious excipient selection based on the understanding of excipient–moisture interactions to maximize the chemical stability of moisture-sensitive drugs. Mannitol-coated HPMC is a promising addition to the formulator’s toolbox for the formulation of controlled release dosage forms by direct compression.
Introduction
Hydroxypropyl methylcellulose (HPMC) is one of the most commonly used hydrophilic polymers in formulations of matrix tablets for controlled release applications [1]. Despite its ubiquity, issues with poor flowability render HPMC challenging to use for direct compression [2,3]. The attraction of employing direct compression for producing HPMC matrices stems not only from using an efficient and cost-effective manufacturing process but also from avoiding wet granulation of a highly viscous polymer. In addition, direct compression is ideal for heat or moisture-sensitive drugs [4,5]. Several companies developed direct compression-grade HPMC, such as METHOCEL™ DC2 (Colorcon) [6], Benecel™ DC (silicified HPMC, Ashland) [7], and RetaLac® (co-processed HPMC–lactose, Meggle) [8], which were shown to deliver improved flow and compression attributes. However, the impact of hygroscopic HPMC when formulated with moisture-sensitive drugs is not well understood. It is generally perceived that a material that absorbs more than 5% moisture at relative humidities below 60% is considered hygroscopic [9].
A drug product should be stable in terms of its chemical, physical, and microbiological properties during its shelf life [10]. Chemical instability, in particular, is characterized by the reduction in labeled drug content and the presence of degradants. Drug degradation typically occurs by hydrolysis, oxidation, photolysis, or photodegradation [11]. Of these, hydrolysis of esters, amides, and carbamates is a major cause of degradation among active pharmaceutical ingredients [12]. Drug hydrolysis in solid dosage form occurs in the presence of moisture, from the initial moisture content of individual components used, or moisture from the external environment [11]. Drug degradation may compromise the safety and efficacy of drug products. In general, drug content should be within 5% w/w of its initial value and the presence of certain degradation products should be within pre-determined limits during its shelf-life [13].
In a finished product, drug stability can be maintained by the avoidance of adventitious environmental moisture through the use of moisture barriers in the form of product packaging [14], tablet coatings [15] and the inclusion of intra-package desiccants [12]. However, such mitigation strategies often incur additional costs. It is therefore desirable to employ a more cost-effective approach through formulation adjustments. For example, the use of starch as an intra-tablet desiccant that preferentially absorbs moisture has been proposed due to the presence of numerous hydroxyl groups coupled with open conformation that permit water entry [16]. This restricts the mobility of water molecules for hydrolysis reactions, thereby enhancing drug stability [17]. It is also notable that moisture in excipients may be transferred to drug particles when relative humidity (RH) in the microenvironment of the dosage form is altered, or by adsorbed moisture at the boundaries between excipient and drug particles [18]. Hence, it would be best to limit the formulation’s initial moisture content, which could be achieved by designing co-processed materials with low hygroscopicity while maintaining desired functionalities. For example, an anti-hygroscopic effect was demonstrated through particle surface coverage by crystalline L-leucine, which imparted resistance to the negative impact of moisture on aerosolization performance [19]. It was separately found that 96.5% of the particle surface could be shielded when using only 50% w/w of the hydrophobic material for effective moisture protection [20]. A similar approach was also reported whereby a coating of polyethylene glycol was applied to reduce the hygroscopicity of sodium carbonate, and it significantly improved flowability and processability [21].
Mannitol has one of the lowest hygroscopicities among commonly used tablet fillers [22]. It is a naturally occurring six-carbon sugar alcohol and is produced commercially by hydrogenation of fructose [23,24], most commonly derived from maize, wheat, or tapioca starches [25]. It is widely used in pharmaceutical formulations due to its chemical inertness, good physiological compatibility, and high compactability [22,26]. Micronized crospovidone co-grounded with mannitol had reduced hygroscopicity while maintaining good tablet physical stability [27]. Mannitol has also been added to poly(vinyl alcohol) tablet coatings to impart moisture-protective properties [28]. It is therefore interesting to explore the use of mannitol-coated HPMC particles as a moisture barrier to enable the formulation of moisture-sensitive drugs for controlled release.
In a previous study, co-processed HPMC–mannitol produced by spray coating mannitol over HPMC was shown to exhibit improved flowability, good tabletability, and maintained flexibility to obtain desired release profiles [29]. Despite the widespread use of HPMC, its impact on the stability of moisture-sensitive drugs has not been investigated. Furthermore, any change in excipients should be carefully evaluated with adequately designed stability studies. Aspirin is selected as the model for moisture-sensitive drugs due to its susceptibility to hydrolysis, which can be used to elucidate the impact of moisture on chemical degradation. This study aims to understand the effects of mannitol-coating on the moisture sorption properties of HPMC and the impact on the stability of HPMC-based tablets. Both open and closed dish conditions were used to evaluate drug stability under accelerated stability conditions (40 °C, 75% RH), with open conditions to mimic bottle packaging and closed conditions to mimic individually packed blisters.
Download the full article as PDF here Mannitol-Coated Hydroxypropyl Methylcellulose as a Directly Compressible Controlled Release Excipient for Moisture-Sensitive Drugs
or read it here
Materials
Direct compression grade HPMC (HPMC DC; METHOCEL™ DC2 K4M, HPMC 2208, 4000 mPa.s grade, Colorcon, Harleysville, PA, USA) was used as received. Co-processed HPMC–mannitol, prepared at a 70:30 ratio (H70M30–CP) and 50:50 ratio (H50M50–CP) were kind gifts from Roquette, France. These co-processed excipients were prepared using a spray-drying tower, where mannitol syrup was sprayed onto fluidized HPMC particles (Benecel™ K4M CR, Ashland, Wilmington, DE, USA) and simultaneously dried. As references for comparison, physical mixtures of HPMC DC and spray-dried mannitol (PEARLITOL® 100 SD, Roquette, Lestrem, France) at different ratios were prepared. The ratio of HPMC and mannitol was varied at 70:30 and 50:50 to obtain H70M30–PM and H50M50–PM physical mixtures, respectively. Physical mixtures were prepared by blending HPMC and mannitol at the respective ratios in a tumble blender (Turbula®, WAB, Basel, Switzerland) at 42 rpm for 10 min. Aspirin (Euro Chemo-Pharma, Perai, Malaysia) was used as the model moisture-sensitive drug as its degradation products and mechanism of degradation in the solid state have been well characterized [35,50,53]. Magnesium stearate (MgSt; Productos Metalest, Zaragoza, Spain) was the tableting lubricant.
Lithium chloride and sodium chloride solutions (Meter Group, Pullman, WA, USA) were used for the calibration of the water activity meter (Aqualab 4TEV, Meter Group, Pullman, WA, USA). Salicylic acid (Sigma-Aldrich, Burlington, MA, USA) was used to prepare calibration standards for the quantification of aspirin degradation products by high-performance liquid chromatography (HPLC). Acetonitrile (J.T. Baker, Phillipsburg, NJ, USA), ortho-phosphoric acid (Sigma-Aldrich, Buchs, Switzerland), and purified water (Advantage A10, MilliQ, Burlington, MA, USA) were used to prepare the mobile phase for HPLC analyses. Dichloromethane (Merck, Darmstadt, Germany) and isopropyl alcohol (Avantor Performance Materials, Alberta, Canada) were used for particle sizing by laser diffractometry.
Kang, C.Y.X.; Chow, K.T.; Lui, Y.S.; Salome, A.; Boit, B.; Lefevre, P.; Hiew, T.N.; Gokhale, R.; Heng, P.W.S. Mannitol-Coated Hydroxypropyl Methylcellulose as a Directly Compressible Controlled Release Excipient for Moisture-Sensitive Drugs: A Stability Perspective. Pharmaceuticals 2024, 17, 1167. https://doi.org/10.3390/ph17091167
Read also our introduction article:
CPHI Milan 2024 – with a focus on excipients
