International journal of pharmaceutics: X 2 (2020): 100042.
Amorphous Solid Dispersions (ASDs) are widely used bioavailability enhancing formulations for drugs with low solubility and/or slow dissolution rate in gastrointestinal fluids (Van den Mooter, 2012). ASDs comprise an amorphous drug dispersed within a matrix. The amorphous drug provides greater aqueous solubility to aid absorption relative to the crystalline form. The matrix is typically a polymer that acts to stabilize the drug in the amorphous state during storage and in gastrointestinal (GI) fluids (Brouwers et al., 2009; Konno and Taylor, 2006; Taylor and Zhang, 2016).Drugs with a low glass transition temperature (Tg) and a high ratio of melting point (Tm) to Tg (Tm/Tg (K/K)) tend to recrystallize due to an overall high driving force and low kinetic barrier to crystallization (Friesen et al., 2008). A drug with a high Tm requires high thermal energy to break the crystal lattice, which generally results in a high energy difference between the crystalline and amorphous forms of the drug. This high energy difference can lead to a high thermodynamic driving force for the drug to convert to the lower energy crystalline state. A low Tg indicates a high degree of molecular mobility and therefore a low kinetic barrier to crystallization.Low Tg, rapidly crystallizing drugs often need a high percentage of dispersion polymer in the ASD to adequately stabilize the drug in the solid state and in solution (Baghel et al., 2016),(Ting et al., 2015; Ullrich and Schiffter, 2018). For example, a dispersion polymer loading of 75% is common, with dispersion polymer loadings of up to 90-95% being reported. The high percentage of dispersion polymer in the ASD not only results in low drug loading but can also cause poor disintegration. ASDs compressed into tablets may disintegrate slowly when the ASD loading in the tablet exceeds 30-70% (Démuth et al., 2015), (Agrawal et al., 2016). Poor disintegration is particularly common for neutral polymers, such as polyvinylpyrrolidone (PVP, e.g. K30 grade), polyvinylpyrrolidone vinyl acetate (PVP VA, i.e. VA 64 grades) and hydroxypropyl methylcellulose (HPMC, e.g. E3 grade) that are soluble across the GI pH range. These polymers hydrate immediately upon introduction into the stomach, resulting in a higher propensity to gel compared to polymers such as Eudragit L100 and HPMCAS that are nearly insoluble at low gastric pH (Goddeeris et al., 2008). Due to the tendency for ASDs to gel, a relatively high fraction of excipients must be added to the tablet formulation to facilitate more rapid disintegration. The addition of certain types of inorganic salts to the formulation has been shown to decrease gelling and improve drug release from ASD tablets (Takano et al., 2019) (Hughey et al., 2013) (Kajiyama et al., 2008). Due to the combined factors of low drug loading in the ASD, and low ASD loading in the tablet, a high tablet mass or multiple tablet units (i.e. tablet burden) is often required to deliver the prescribed dose.The acceptable tablet size and number of units depend upon several criteria. For example, dose, indication, age of the targeted population (e.g., adult, pediatric, geriatric), healthy or disease state, desired market image and drug product life cycle all need to be considered. For high dose drugs, tablet burden may be a significant issue. According to Pharmacircle, 24% of all prescription drug products marketed worldwide, including amorphous and non-amorphous drug substances, have doses of 200 mg or greater (PharmaCircle, 2018). Of 22 FDA-approved ASD drug products surveyed according to the maximum dosage strength, more than 50% of these ASD products have maximum dosage strengths greater than 100 mg (Stewart et al., 2020 (in press)). In some cases, accommodating a 100 mg dosage strength for an ASD drug product could require a high tablet mass, which could result in poor patient compliance or be untenable for pediatric and geriatric populations. The tablet mass required to achieve a given dose is determined by the drug loading in the ASD and the ASD loading in the tablet. Typical ASD drug loadings range from 10 - 40%, whereas ASD loadings in the tablet often range from 40 - 80%. Assuming these ranges, a total tablet mass of 300 - 2500 mg would be required to achieve a 100 mg active dose in a single dosage unit. For example, a 25% active ASD with a 50% ASD loading would result in a total tablet mass of 800 mg to achieve a 100 mg active dose. The 100 mg dosage strength of the commercial spray dried ASD tablet, Intelence®, has an 800 mg total mass (Voorspoels and Jans, 2008). ASD drug products indicated for infections are likely to require strategies for limiting tablet burden, as 56% of current drug products indicated for infections have doses of 200 mg or greater (PharmaCircle, 2018).To address high tablet burden, a strategy was developed to maximize the percentage of drug in a rapidly disintegrating ASD dosage form for low Tg, rapidly crystallizing drugs. In this approach, a drug is spray dried with a high Tg polymer to facilitate high drug loading in the ASD (Babcock W, 2013). To extend drug supersaturation in solution, a concentration sustaining polymer (CSP) is granulated with the ASD prior to tableting (Ozaki et al., 2013) (Xie and Taylor, 2016). In this study, the enteric polymer, poly(methyl methacrylate-co-methacrylic acid) (1:1) (Eudragit® L100, Evonik Industries, Essen, Germany) (Tg = 187°C) Eudragit® L100 was selected as the dispersion polymer due to its high Tg, which is 30-70 °C higher than common dispersion polymers such as HPMCAS, PVP, PVP VA and HPMC (Shepard et al., 2020). Hydroxypropyl methylcellulose acetate succinate (HPMCAS) (Tg = 119°C) H grade was chosen as the CSP. HPMCAS is a particularly effective CSP due its amphiphilic nature when ionized at small intestinal pH. At pH > ~5, hydrophobic regions of HPMCAS can interact with hydrophobic drugs, and carboxylate groups can interact with the aqueous phase at the drug-water interface to inhibit crystal nucleation and growth (Mosquera-Giraldo et al., 2016) (Price et al., 2019) (Friesen et al., 2008). The H grade of HPMCAS H was chosen for this study since it has the highest percentage of hydrophobic acetyl substitution of the standard HPMCAS grades, allowing it to interact most effectively with hydrophobic drugs. Compared to HPMCAS, Eudragit L100 is typically a less effective CSP. Potential factors contributing to its relative ineffectiveness as a CSP include its hydrophilicity and lack of branches or bulky groups for forming favorable polymer-drug interactions (Mosquera-Giraldo et al., 2016) (Ilevbare et al., 2013).This work describes use of the HLDF architecture to reduce tablet mass by 40% compared to a typical approach. In a typical ASD formulation the dispersion polymer(s) enables both solid-state physical stability and dissolution rate and/or concentration sustainment in GI fluids. In contrast, the HLDF architecture combines two different polymers, one inside and one outside the ASD to achieve physical stability and concentration sustainment. HLDF and typical 'benchmark' ASDs were assessed for physical stability and tablets were assessed for in vitro dissolution performance. Manufacturability of the HLDF tablets was assessed by characterizing tablet attributes after manufacturing at the kilogram scale and assessing flow and mechanical properties of the final blend. Physical stability and in vitro performance were found to be comparable for the HLDF and benchmark formulation approaches, and excellent downstream manufacturability was demonstrated for the HLDF architecture.
