pharmaceutics Review Crystallization Tendency of Pharmaceutical Glasses: Relevance to Compound Properties, Impact of Formulation Process, and Implications for Design of Amorphous Solid Dispersions Kohsaku Kawakami World Premier International Research Center for Materials Nanoarchitectonics (WPI-MANA), National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan; [email protected]; Tel.: +81-29-860-4424 Received: 2 April 2019; Accepted: 24 April 2019; Published: 1 May 2019 Abstract: Amorphous solid dispersions (ASDs) are important formulation strategies for improving the dissolution process and oral bioavailability of poorly soluble drugs. Physical stability of a candidate drug must be clearly understood to design ASDs with superior properties. The crystallization tendency of small organics is frequently estimated by applying rapid cooling or a cooling/reheating cycle to their melt using differential scanning calorimetry. The crystallization tendency determined in this way does not directly correlate with the physical stability during isothermal storage, which is of great interest to pharmaceutical researchers. Nevertheless, it provides important insights into strategy for the formulation design and the crystallization mechanism of the drug molecules. The initiation time for isothermal crystallization can be explained using the ratio of the glass transition and storage temperatures (Tg/T). Although some formulation processes such as milling and compaction can enhance nucleation, the Tg/T ratio still works for roughly predicting the crystallization behavior. Thus, design of accelerated physical stability test may be possible for ASDs. The crystallization tendency during the formulation process and the supersaturation ability of ASDs may also be related to the crystallization tendency determined by thermal analysis. In this review, the assessment of the crystallization tendency of pharmaceutical glasses and its relevance to developmental studies of ASDs are discussed. Keywords: pharmaceutical glass; crystallization tendency; crystallization; nucleation; milling; accelerated stability test 1. Introduction Amorphous solid dispersions (ASDs) are among of the most effective enabling formulations for improving the dissolution process and therefore the oral absorption of poorly soluble drugs [1–7]. Because of their high energy, amorphous solids can reach a supersaturated state during their dissolution process. Although solubilization techniques that increase the equilibrium solubility, including the use of micelles and organic solvents, can inhibit membrane permeation [8,9], it does not happen for supersaturated systems originated from ASDs [10]. It is now widely recognized that the supersaturation created by ASDs can cause phase separation into concentrated and diluted phases, based on the spinodal decomposition mechanism, followed by the formation of a quasi-equilibrium colloidal structure consisting of a concentrated dispersed phase suspended in a diluted continuum phase [11,12]. Although the role of the dispersed phase in the oral absorption is still under debate, this process can maintain high levels of supersaturation for the continuum phase, which are beneficial for oral absorption [13]. The stability of the colloidal phase is significantly influenced by the polymer Pharmaceutics 2019, 11, 202; doi:10.3390/pharmaceutics11050202 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2019, 11, 202 2 of 17 speciesPharmaceutics [13–15]. 2018 Since, 10, x the FOR supersaturation PEER REVIEW behavior of ASDs, including phase separation and2 its of impact17 on membrane transport and oral absorption, are outside the scope of this review, readers interested in theseinfluenced aspects are by referredthe polymer to recent species studies [13–15]. [11 Since,13,16 the–18 supersaturation] for further details. behavior of ASDs, including phase separation and its impact on membrane transport and oral absorption, are outside the scope Drug molecules in ASDs must remain in the amorphous state to exert their beneficial effects during of this review, readers interested in these aspects are referred to recent studies [11,13,16–18] for the dissolution process. Even a trace amount of crystals would undermine these favorable effects, further details. because itDrug induces molecules crystallization in ASDs must after remain suspension in the ofamorphous the ASD state in aqueous to exert mediatheir beneficial [19,20]. Polymericeffects excipientsduring inthe ASDs dissolution serve notprocess. only Even for improving a trace amou thent supersaturationof crystals would behaviorundermine as these mentioned favorable above, but alsoeffects, for because inhibiting it induces crystallization crystallization of the after drug. suspension Miscibility of the is anASD important in aqueous factor media for [19,20]. exploiting the stabilizationPolymeric excipients effect by in the ASDs polymer serve [21not–23 only]. Obviously, for improving the crystallizationthe supersaturation tendency behavior of the as drug moleculementioned itself isabove, another but importantalso for inhibiting factor a ffcrystallizationecting the storage of the stability. drug. Miscibility is an important factorTable 1for summarizes exploiting the generally stabilization accepted effect ideas by the for polymer good glass [21–23]. formers Obviously, in the casethe crystallization of small organic compounds.tendency Goodof the glassdrug molecule formers tenditself tois another have a largeimportant molecular factor affecting weight [ 24the]; storage other chemical-structural stability. propertiesTable of these 1 summarizes compounds generally include accepted a low number ideas for of good benzene glass rings, formers a high in the degree case ofof molecularsmall organic compounds. Good glass formers tend to have a large molecular weight [24]; other asymmetry, as well as large numbers of rotatable bonds, branched carbon skeletons, and electronegative chemical-structural properties of these compounds include a low number of benzene rings, a high atoms [25–27]. Specific tendencies can be found for the physicochemical properties as well. Good glass degree of molecular asymmetry, as well as large numbers of rotatable bonds, branched carbon formersskeletons, should and have electronegative a high melting atoms temperature [25–27]. Specific and enthalpy tendencies/entropy, can asbe wellfound as afor large the free energyphysicochemical difference between properties crystalline as well. andGood amorphous glass formers states should [26 ].have Fragility a high [ 28melting,29], which temperature quantifies the degreeand enthalpy/entropy, of non-Arrhenius as well behavior as a large of free a en glass,ergy difference is another between parameter crystalline that and can amorphous correlate with the crystallizationstates [26]. Fragility tendency [28,29], [26 which,30,31 quantifies]. However, the degree it should of non-Arrhenius be emphasized behavior that the of crystallizationa glass, is tendencyanother of aparameter certain compound that can correlate is frequently with determined the crystallization by observing tendency its crystallization[26,30,31]. However, during it rapid coolingshould or cooling be emphasized/reheating that cycles the using crystallization differential tendency scanning ofcalorimetry, a certain compound which does is notfrequently necessarily reflectdetermined easiness ofby theobserving isothermal its crystallization crystallization, during which rapid is cooling of interest or cooling/reheating for pharmaceutical cycles researchers. using The didifferentialfference between scanning hot calorimetry, (non-isothermal) which does and isothermalnot necessarily crystallization reflect easiness is schematically of the isothermal illustrated crystallization, which is of interest for pharmaceutical researchers. The difference between hot in Figure1. Hot crystallization proceeds upon a decrease in free volume, and each molecule has a (non-isothermal) and isothermal crystallization is schematically illustrated in Figure 1. Hot relatively high conformational flexibility during the crystallization. On the other hand, isothermal crystallization proceeds upon a decrease in free volume, and each molecule has a relatively high crystallizationconformational occurs flexibility under during almost the constant crystallization. volume, On and the the other molecular hand, isothermal motion iscrystallization more restricted. Crystallizationoccurs under can almost only beconstant achieved volume, after and overcoming the molecular the energetic motion is barrier more re tostricted. structural Crystallization transformation, in whichcan only noncovalent be achieved “weak” after overcoming interactions the play energeti an importantc barrier to role, structural unlike transformation, in inorganic glasses. in which noncovalent “weak” interactions play an important role, unlike in inorganic glasses. Table 1. Features of good glass formers based on small organic molecules. Table 1. Features of good glass formers based on small organic molecules. Chemical-Structural Features Physicochemical Features Chemical-Structural Features Physicochemical Features Large molecularLarge molecular weight weight Large Large melting melting enthalpy/entropy enthalpy/entropy Low numberLow of number benzene of benzene rings rings High High melting melting temperature temperature Low symmetryLow symmetry Large Large crystal/amorphous crystal/amorphous energy energy difference difference Large numberLarge