(640a) Possible Synergistic Effects of Binary Polymers in Enhancing Release of a Poorly Soluble Drug from Amorphous Solid Dispersions

Over the last few decades, majority of the new chemical entities (NCEs) in the drug discovery pipeline are poorly-water soluble [1], and their slow dissolution turns out to be the rate-limiting step during intestinal absorption. Formulating a drug in its amorphous form could significantly enhance the dissolution rate as it has higher apparent solubility [2]. Despite its potential benefit, the application of pure amorphous form is limited due to its inherent thermodynamic instability. Polymers are often incorporated to form amorphous solid dispersions (ASDs) with the intent of providing stability during processing, storage, and dissolution. They play an important role in inhibiting the recrystallization in both the matrix and the dissolution medium; thus, they allow for supersaturation generation during dissolution.

Selection of a proper polymer/surfactant system for ASD formulations is essential to achieving storage stability and dissolution enhancement. It is well-known that most polymers used in ASDs are relatively hydrophobic and dissolve slowly, which leads to slow drug release from ASDs. To resolve this issue, surface-active agents such as surfactants have been used alone or in combination with polymers. The formulations with surfactants exhibited improved dissolution and physical stability compared to those w/o surfactants [3, 4]. However, detrimental effects of surfactants have also been reported [5, 6]. Considering these conflicting findings, a binary polymer system can be an alternative to surfactants in ASDs. Tian and Taylor [7] produced ASD of celecoxib (CXB) and compared the effectiveness of binary polymer system with that of the single polymer. Polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPMC), and HPMC acetate succinate (HPMCAS) were used as polymers. Combining cellulosic polymers with PVP enabled improved CXB release and prevented recrystallization more effectively than single polymers. Recently, other studies have also shown the effectiveness of polymer combination in the dissolution performance of ASD and recrystallization inhibition from supersaturated solution over single polymer [8–10]. Only a few studies have investigated binary polymer system in ASDs systematically. In these studies, supersaturation generation and recrystallization inhibition properties of the binary polymer systems have been the main focus; however, the wetting effectiveness of the individual polymer and their combination has not received much attention. It is hypothesized that wettability enhancement of the hydrophobic drug, as modulated by the polymers, could also affect drug release rate from the ASDs. This aspect should be considered besides the impact of polymers on supersaturation generation and maintenance, and their recrystallization inhibition property.

The aim of this study is to examine the effectiveness of binary polymers vs. single polymer in the production of spray-dried ASD of a poorly water-soluble drug, Griseofulvin (GF). GF has an aqueous solubility of 14.5 mg/L at 37 ^oC. Hydroxypropyl cellulose (HPC), Soluplus® (Sol), and Vinylpyrrolidone–Vinyl acetate (Kollidone VA64) were used as polymers. For all formulations, drug:polymer ratio was fixed at 1:3. Combination of VA64–HPC, Sol–HPC, and Sol–VA64 were used for the binary polymer systems. Acetone–deionized water mixture was used to dissolve GF–Sol, GF–HPC, and GF–HPC–Sol formulation. On the other hand, mixture of acetone–ethanol–deionized water was used to dissolve GF–VA64, GF–VA64–HPC, and GF–Sol–VA64 formulation. Completely dissolved drug–polymer (s) solutions were spray-dried to evaporate the solvents and produce ASD. X-ray powder diffraction (XRPD), modified Washburn experiments, drug desupersaturation experiments, and in vitro USP II dissolution testing were used for the characterization of the spray-dried powders. Dissolution tests were performed with a USP II apparatus by dispersing 100 mg GF in 1000 mL deionized water at 37 ºC.

XRPD results suggest that the spray-drying of GF–polymer(s) solutions produced ASDs for all polymers used. The dissolution tests on ASDs with a single polymer reveal that relatively low supersaturation ratios (as percentages), i.e., 42% and 33%, were achieved respectively byVA64 and HPC, whereas notable supersaturation (163%) was generated by Sol at 210 min albeit at a slower GF release rate. This could be explained by fast recrystallization of GF in the dissolution medium and/or ASD matrix when VA64 or HPC was used alone, and Sol appeared to be an effective recrystallization inhibitor. The solubility parameter difference for the GF–polymer pairs were estimated as follows: 7.2, 7.5, and 11.8 MPa^0.5, respectively, for GF–Sol, GF–VA64, and GF–HPC. The poor miscibility of GF with HPC could explain the observed lower extent of supersaturation and faster recrystallization than those for Sol. The desupersaturation experiments showed that HPC and VA64 cannot maintain supersaturation; hence, they are poor recrystallization inhibitors in the solution. While Sol appears to be a good recrystallization inhibitor, due to slow release of GF from the Sol matrix, the supersaturation in the dissolution medium built up slowly. The faster GF release from VA64 and HPC matrices than for Sol matrix can be explained by the more hydrophilic nature of the former, as quantified by the higher wetting effectiveness factors calculated via the modified Washburn method, and faster erosion of the former polymers compared to the Sol.

With some exceptions, the dissolution behavior of the ASDs could be elucidated based on the performance of ASDs with single polymers. Despite higher supersaturation ratios attained at 210 min (58%–77% for different mass ratios of VA64–HPC) compared with the single polymers, VA64–HPC combination was still inferior to Sol alone in terms of recrystallization inhibition. This is of no surprise as neither VA64 nor HPC inhibited recrystallization and maintained supersaturation—as independently confirmed by desupersaturation experiments. When Sol was combined with either HPC or VA64, more hydrophilic polymers, the supersaturation levels were higher than those obtained with VA64–HPC. This result shows the criticality of having at least a major polymer, (Sol here), that has good miscibility with the drug and that can inhibit recrystallization in the polymer matrix and maintain supersaturation in the dissolution medium. When the more hydrophilic polymer (HPC or VA64) was added to Sol, the dissolution rate increased as compared with that of Sol alone. For Sol–HPC, a decrease in Sol:HPC mass ratio led to faster GF release, but lower extent of supersaturation. This observation can be explained by more effective wettability enhancement, but poor recrystallization inhibition capability of HPC both in the matrix (due to poor GF–HPC miscibility leading to phase separation) and in the dissolution medium. On the other hand, for Sol–VA64, a decrease in Sol:VA64 mass ratio led to faster GF release. The supersaturation at 210 min was lower for Sol:VA64 mass ratios of 1:1 and 1:5 than that for Sol alone, but surprisingly both the GF release rate and the supersaturation ratio at 210 min (222% vs. 163%) were higher for Sol:VA64 mass ratio of 5:1 than those for Sol alone and VA64 alone. Apparently, a synergistic effect of Sol–VA64 combination exists when Sol was used in excess of VA64.

This study has demonstrated that the use of a binary polymer system in drug ASDs could result in synergistic positive effects on the drug release rate and extent of supersaturation. The synergy occurs when both polymers are miscible with the drug, the major polymer (Sol) is an excellent recrystallization stabilizer in the dissolution medium, and the minor polymer (VA64), being more hydrophilic, could bring significant wettability enhancement to the hydrophobic drug (GF). These findings could help formulators in rational design of immediate-release drug ASDs with binary polymers, obviating the need for surfactants.

References

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