The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers.

Lasse Blaabjerg,Korbinian Löbmann,Eleanor Lindenberg,Holger Grohganz,Thomas Rades,Anette Müllertz

doi:10.3390/pharmaceutics10040164

Lasse Blaabjerg, Korbinian Löbmann + Show 4 more

Open Access

https://doi.org/10.3390/pharmaceutics10040164

Copy DOI

Abstract

The increasing number of poorly water-soluble drug candidates in pharmaceutical development is a major challenge. Enabling techniques such as amorphization of the crystalline drug can result in supersaturation with respect to the thermodynamically most stable form of the drug, thereby possibly increasing its bioavailability after oral administration. The ease with which such crystalline drugs can be amorphized is known as their glass forming ability (GFA) and is commonly described by the critical cooling rate. In this study, the supersaturation potential, i.e., the maximum apparent degree of supersaturation, of poor and good glass formers is investigated in the absence or presence of either hypromellose acetate succinate L-grade (HPMCAS-L) or vinylpyrrolidine-vinyl acetate copolymer (PVPVA64) in fasted state simulated intestinal fluid (FaSSIF). The GFA of cinnarizine, itraconazole, ketoconazole, naproxen, phenytoin, and probenecid was determined by melt quenching the crystalline drugs to determine their respective critical cooling rate. The inherent supersaturation potential of the drugs in FaSSIF was determined by a solvent shift method where the respective drugs were dissolved in dimethyl sulfoxide and then added to FaSSIF. This study showed that the poor glass formers naproxen, phenytoin, and probenecid could not supersaturate on their own, however for some drug:polymer combinations of naproxen and phenytoin, supersaturation of the drug was enabled by the polymer. In contrast, all of the good glass formers—cinnarizine, itraconazole, and ketoconazole—could supersaturate on their own. Furthermore, the maximum achievable concentration of the good glass formers was unaffected by the presence of a polymer.

Highlights

The increased focus on combinatorial chemistry and high-throughput screening in drug discovery has led to an increase in poorly aqueous soluble drug candidates, with low and variable bioavailability in pharmaceutical development [1]
Cinnarizine, itraconazole and ketoconazole could be prepared in an amorphous form using cooling rates of the melt below 2 K/min and are class 3 drugs with respect to glass forming ability (GFA), i.e., good glass formers (Table 1)
The inherent supersaturation potential of the same drugs was determined by the use of a solvent shift method using the μ-Diss Profiler to induce supersaturation of the drug in the absence or presence of predissolved polymer in fasted state simulated intestinal fluid (FaSSIF)

Summary

Introduction

The increased focus on combinatorial chemistry and high-throughput screening in drug discovery has led to an increase in poorly aqueous soluble drug candidates, with low and variable bioavailability in pharmaceutical development [1]. A classification system of GFA based on the recrystallization tendency of drugs during cooling and heating cycles has previously been proposed [4]. GFA class 3 drugs neither recrystallized during cooling of the melt at 20 K/min nor during the following heat cycle at 10 K/min [4]. Classes 1, 2 and 3 represent poor, modest and good glass formers, respectively. This classification system based on arbitrary categories was further substantiated in a later study that revealed that the drugs can be classified according to their inherent crystallization tendency independent of the predefined categories [5]. GFA class 1 drugs inherently have critical cooling rates above 750 K/min, GFA class 2 drugs have critical cooling rates between 10 and 20 K/min and GFA class 3 drugs have critical cooling rates below 2 K/min [5,6]

Objectives

Methods

Results

Conclusion