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 and 2 its of impact 17 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 of number rotatable of rotatable bonds bonds Large Large fragility fragility High branching degree Large T /T High branching degree Large Tg/Tmg m Large number of electronegative atoms Large viscosity above T Large number of electronegative atoms Large viscosity above Tg g

Tg, glass transitionTg, glass temperature; transition T temperature;m, melting temperature.Tm, melting temperature.

Figure 1. Schematic representation of hot (non-isothermal) and isothermal crystallization.

Pharmaceutics 2018, 10, x FOR PEER REVIEW 3 of 17 Pharmaceutics 2019, 11, 202 3 of 17 Figure 1. Schematic representation of hot (non-isothermal) and isothermal crystallization.

TheThe followingfollowing sectionssections reviewreview thethe crystallizationcrystallization tendency of pharmaceutical glasses, glasses, with with emphasisemphasis on on relationship relationship with with their their chemical chemical structure, structure, remark remark on on its its evaluation evaluation process, process, relevance relevance for glassfor glass properties properties including including the storage the stabilitystorage (i.e.,stability isothermal (i.e., isothermal crystallization), crystallization), relevance to relevance manufacture, to andmanufacture, possible correlation and possible with correlation the supersaturation with the supersaturation ability. In addition ability. to discussion In addition on to ideal discussion glasses thaton canideal be glasses prepared that by can melt–quench be prepared procedure, by melt–quench the stability procedure, of real the glasses, stability which of real are glasses, prepared which through are formulationprepared through process formulation such as milling, process is alsosuch discussed. as milling, is also discussed.

2.2. Classification Classification of of Crystallization Crystallization TendenciesTendencies InIn the the field field of pharmaceutical of pharmaceutical sciences, sciences, many researchmany groupsresearch have groups evaluated have the evaluated crystallization the tendencycrystallization of drug tendency molecules of bydrug applying molecules a cooling by applying/reheating a cyclecooling/reheating to the melt in cycle a diff erentialto the melt scanning in a calorimetrydifferential (DSC)scanning [26 calorimetry,32]. The following (DSC) [26,32]. classification, The following as proposed classification, by Taylor as proposed et al. [26], by is Taylor widely recognized:et al. [26], is widely recognized:

ClassClass 1: 1: CompoundsCompounds thatthat crystallizecrystallize duringduring cooling from the melt at 20 °C/min.◦C/min. ClassClass 2:2: CompoundsCompounds thatthat dodo notnot crystallizecrystallize during cooling from the the melt, melt, but but crystallize crystallize during during subsequentsubsequent reheating reheating at at 10 10◦ °C/min.C/min. Class 3: Compounds that do not crystallize during the cooling/reheating cycle mentioned above. Class 3: Compounds that do not crystallize during the cooling/reheating cycle mentioned above. Examples are shown in Figure2. Haloperidol, a Class 1 compound, always crystallizes at Examples are shown in Figure 2. Haloperidol, a Class 1 compound, always crystallizes at 100 100 C during cooling from the melt, regardless of the cooling rate achievable by conventional DSC °C ◦during cooling from the melt, regardless of the cooling rate achievable by conventional DSC (Figure2a) [ 33], which means that crystallization is entirely governed by the temperature. It should be (Figure 2a) [33], which means that crystallization is entirely governed by the temperature. It should noted that the crystallization temperature of some Class 1 compounds such as tolbutamide depends be noted that the crystallization temperature of some Class 1 compounds such as tolbutamide on the cooling rate [33]. Class 1 compounds can be further divided into two groups according to their depends on the cooling rate [33]. Class 1 compounds can be further divided into two groups crystallization behavior during cooling in liquid nitrogen, whereby compounds that crystallize and according to their crystallization behavior during cooling in liquid nitrogen, whereby compounds remainthat crystallize amorphous and are remain categorized amorphous as Class are 1a categorized and Class 1b,as Class respectively 1a and [Class34]. This 1b, direspectivelyfference is likely[34]. toThis be analogousdifference is to likely the dependence to be analogous of the to crystallization the dependence temperature of the crystallization on the cooling temperature rate mentioned on the above,cooling that rate is, mentioned haloperidol above, and that tolbutamide is, haloperidol can be and identified tolbutamide as Class can 1abe andidentified Class as 1b Class compounds, 1a and respectively.Class 1b compounds, In the case respectively. of haloperidol, In the crystallization case of haloperidol, is inhibited crystallization when the meltis inhibited is cooled when at a the rate fastermelt is than cooled 100 at◦C a/s rate to producefaster than a mesophase 100 °C/s to [produce33]. Acetaminophen, a mesophase [33]. a Class Acetaminophen, 2 compound, a does Class not 2 crystallizecompound, during does cooling,not crystallize but crystallizes during cooling, during thebut subsequentcrystallizes reheatingduring the (Figure subsequent2b). Fenofibrate, reheating a(Figure Class 3 2b). compound, Fenofibrate, does a Class not crystallize 3 compound, during does the not cooling crystallize/reheating during cycle the cooling/reheating (Figure2c). Tables cycle2–4 summarizes(Figure 2c). examplesTables 2–4 of Tablecompounds 2 Table 3 Table 4 summarizes belonging examples to each of class. compounds belonging to each class.

(a) (b) (c)

FigureFigure 2.2. ExamplesExamples of coolingcooling/reheating/reheating differential differential scanning calorimetry calorimetry (DSC) (DSC) curves curves from from the the melt:melt: ((aa)) coolingcooling curvescurves ofof haloperidolhaloperidol (Class 1) 1) at at various various cooling cooling rates, rates, as as indicated indicated in in the the figure; figure; (b(b)) cooling cooling/reheating/reheating curves curves of acetaminophenof acetaminophen (Class (Class 2); and 2); (c )and cooling (c) /reheatingcooling/reheating curves of curves fenofibrate of (Classfenofibrate 3). (Class 3).

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Table 2. Examples of Class 1 compounds.

Compounds Mw (Da) Tm (◦C) Tg (◦C) Tg/Tm ∆H (kJ/mol) m Reference Antipyrin 188 111 25 0.65 25.2 81 [31] − Anthranilic acid 137 147 5 0.66 22.8 - [26] Atenolol 266 153 22 0.69 37.5 - [26] Atovaquone 367 219 - - 33.5 - [35] Benzamide 121 127 10 0.66 21.7 - [26] − Benzocaine 165 89 31 0.67 22.6 - [26] − Caffeine 194 237 72 0.68 20.8 - [26] Carbamazepine 236 192 61 0.72 25.5 - [26] Chlorpropamide 277 118 17 0.74 27.4 219 [31] Chlorzoxazone 170 191 38 0.67 25.6 - [26] Clofibric acid 215 121 - - 29.0 - [35] Diflunisal 250 213 - - 35.6 - [35] Felbinac 212 164 24 0.68 29.8 - [26] Flufenamic acid 281 135 17 0.71 27.1 78 [26,36] Griseofulvin 353 218 89 0.74 39.1 74 [26,37] Haloperidol 376 152 33 0.72 54.3 - [26] Indoprofen 281 212 50 0.67 36.0 - [26] Lidocaine 234 68 39 0.69 16.7 - [26] − Mefenamic acid 241 231 - - 39.4 - [35] Naproxen 230 157 56 0.77 32.4 - [35,38] Nepafenac 254 183 - - 42.8 - [35] Phenacetin 179 136 2 0.67 31.5 - [26] Piroxicam 331 201 - - 35.6 - [35] Probenecid 285 199 - - 40.4 - [35] Saccharin 183 228 - - 29.5 - [35] Salicylic acid 138 159 - - 24.9 - [35] Theophylline 180 272 94 0.67 29.6 - [26] Tolbutamide 270 128 5 0.69 26.2 122 [31] Tolfenamic acid 262 213 63 0.69 38.8 - [26] Average 237 172 27 0.69 31.1 115 -

Mw, molecular weight; ∆H, melting enthalpy; m, fragility. Although the fragility can be determined by various methods, the evaluation based on the temperature dependence of Tg is preferentially employed because it exhibits the best correlation with the crystallization tendency [31].

Table 3. Examples of Class 2 compounds.

Compounds Mw (Da) Tm (◦C) Tg (◦C) Tg/Tm ∆H (kJ/mol) m Reference Acetaminophen 151 169 23 0.67 27.2 77 [31] Bifonazole 310 149 16 0.68 39.2 76 [31] Celecoxib 381 163 58 0.76 37.4 85 [26] Cinnarizine 369 120 7 0.71 40.9 84 [31] Clofoctol 365 88 4 0.75 35.2 70 [26] − Dibucaine 343 65 35 0.70 29.2 132 [26] − Droperidol 379 143 29 0.73 40.0 108 [26] Flurbiprofen 244 115 5 0.69 27.4 88 [31] − Nifedipine 346 172 46 0.72 38.2 112 [31] Phenobarbital 233 174 42 0.70 28.7 96 [31] Phenylbutazone 308 106 6 0.70 27.6 79 [36] − Tolazamide 311 172 18 0.65 43.4 18 [26] Average 312 136 16 0.71 34.5 85 - Pharmaceutics 2019, 11, 202 5 of 17

Table 4. Examples of Class 3 compounds.

Compounds Mw (Da) Tm (◦C) Tg (◦C) Tg/Tm ∆H (kJ/mol) m Reference Aceclofenac 354 153 10 0.66 42.3 25 [26] Clotrimazole 345 141 28 0.73 33.3 63 [31] Curcumin 368 182 62 0.74 50.1 87 - Felodipine 384 147 45 0.76 31.0 66 [26] Fenofibrate 361 80 19 0.72 33.0 82 [31] − Ibuprofen 206 76 44 0.66 26.5 75 [31] − Indomethacin 358 161 45 0.73 37.6 85 [31] Itraconazole 706 168 58 0.75 57.6 731 [26] Ketoconazole 531 147 44 0.75 52.9 97 [31] Ketoprofen 254 95 3 0.73 28.3 67 [31] − Loratadine 383 134 35 0.76 27.3 72 [31] Miconazole 417 86 1 0.76 32.8 61 [26] Nilutamide 317 155 33 0.72 31.0 106 [26] Nimesulide 308 150 21 0.70 33.4 103 [26] Pimozide 462 219 54 0.66 42.7 170 [26] Probucol 517 126 27 0.75 39.3 138 [39] Procaine 236 61 39 0.70 26.2 90 [31] − Ribavirin 244 168 56 0.75 45.7 70 [40] Ritonavir 721 122 47 0.81 65.3 86 [31] Average 393 135 24 0.73 38.8 120 -

Average parameters are also presented in the table for each class of compounds. The molecular weight shows an increase with increasing classification number, which reflects the importance of the complexity of the molecular structure. The melting enthalpy also increases with increasing classification number, which can be explained in terms of the strength of the molecular interactions. On the other hand, the effect of the melting temperature was opposite to the expectation, while the effect of the fragility was not clear. However, the effect of the fragility is difficult to evaluate, because this parameter could not be calculated for most Class 1 compounds. Moreover, the fragility obtained for chlorpropamide exhibited an unusual value, 219, which significantly influenced the overall average. Figure3 visualizes individual data of molecular weight and melting enthalpy of compounds in each class. Figure3a clearly shows that all compounds with the molecular weight larger than 400 Da are involved in Class 3, whereas the molecules smaller than 200 Da are not included in Class 3 at all. However, molecular weight was found to be the only parameter that shows some extent of correlation with the crystallization tendency, if all the data are plotted, as presented in Figure3. As an example, Figure3b shows relationship between the melting enthalpy and crystallization tendency. Although the averaged values indicated correlation with the crystallization tendency, it is not obviously statistically meaningful. Other structural/thermodynamic parameters did not exhibit any correlations with the crystallization tendency, either. Special attention to molecular weight was also made by Mahlin et al. [24], who found the molecules larger than 300 Da to be good glass formers during formulation processes. Note that the structural feature of compounds that may be correlated with the crystallization tendency, as shown in Table1, has been mainly concluded by observing series of compounds that have similarity in their chemical structure. When variety of compounds is collected for examination, focus on single parameter does not seem to be sufficient. The combination of molecular volume and melting enthalpy was reported to be an excellent predictor of the crystallization tendency by Wyttenbach et al., based on theoretical considerations centered on the so-called Prigogine–Defay ratio [35]. In their study, the trend of the Tg/Tm ratio also agreed with the expected trend; interestingly, the Tg/Tm parameter was also shown to be correlated with the Prigogine–Defay ratio [35,41]. Pharmaceutics 2018, 10, x FOR PEER REVIEW 6 of 17 based on the information described in Table 1 to increase applicability of ASD. As noted below, suppression of crystallization tendency may also be related to increase in supersaturation ability after dissolution. Further understanding on relationship between chemical structure and Pharmaceuticscrystallization2019 , tendency11, 202 should increase options of chemical modification strategy of candidate6 of 17

Pharmaceuticscompounds. 2018 , 10, x FOR PEER REVIEW 6 of 17 based on the information described in Table 1 to increase applicability of ASD. As noted below, suppression of crystallization tendency may also be related to increase in supersaturation ability after dissolution. Further understanding on relationship between chemical structure and crystallization tendency should increase options of chemical modification strategy of candidate compounds.

Figure 3.3. Visualization of:of: ((aa)) molecularmolecular weight; weight; and and ( b()b melting) melting enthalpy enthalpy of of compounds compounds belonging belonging to eachto each class. class.

AAlternatively, common strategy the critical to improve cooling biopharmaceuticalrate for achieving vitrification performance has of also poorly been soluble employed candidates for the includesclassification; increase for example, in hydrophilicity, compounds which that crystallize frequently even has at trade-o 750 °C/minff relationship were classified with aasffi Classnity to1, therapeuticthose with targets.moderate However, crystallization another approachability and may that be suppressioncan be vitrified of crystallization at ca. 10–20 tendency °C/min basedwere on the information described in Table1 to increase applicability of ASD. As noted below, suppression designatedFigure 3.as Visualization Class 2, while of: ( aClass) molecular 3 compounds weight; and only (b) meltingrequire enthalpy a very ofslow compounds cooling belongingrate, below 2 of crystallization tendency may also be related to increase in supersaturation ability after dissolution. °C/min,to each for class.vitrification [38,42]. Despite the different criteria employed, the classifications based on Furtherthis methodology understanding agreed on relationship well with betweenthose in chemicalTables 2–4 structure Table 2 Table 3 and Table 4, crystallizationexcept that tolbutamide tendency should and increasecinnarizineAlternatively, options were of placed chemicalthe critical in Classes modification cooling 2 and rate 3, strategy for respectively achieving of candidate [38].vitrification compounds. has also been employed for the classification;Alternatively,The different for example, behavior the critical compounds of coolingClasses rate1that and forcrystallize 2 achievingcompou evennds vitrification atlikely 750 °C/minreflects has weredifferences also classified been employedin nucleationas Class for 1, thethoseand classification;crystal with growthmoderate for temperatures example,crystallization compounds (Figure ability 4). thatForand Class crystallizethat can1 compounds, be even vitrified at 750 the at◦ Coptimum ca./min 10–20 were nucleation °C/min classified were and as Classdesignatedcrystal 1, growth those as withClass temperatures moderate2, while Classshould crystallization 3 compoundsbe close ability to onlyeach and requireother; that can hence,a bevery vitrified afterslow reachingcooling at ca. 10–20rate,an optimum below◦C/min 2 were°C/min,temperature designated for vitrification where as Classboth [38,42]. 2,nucleation while Despite Class and the 3 compoundscrystal different gr owthcriteria only proceed, require employed, athe very themelt slow classifications can cooling crystallize. rate, based below This on 2 C/min, for vitrification [38,42]. Despite the different criteria employed, the classifications based on thisprocess◦ methodology is expected agreed to be basedwell withon homogeneous those in Tables nucleation. 2–4 Table 2 Table In 3 Tablecontrast, 4, except the that optimum tolbutamide nucleation and thiscinnarizinetemperature methodology were for placedClass agreed 2in wellcompounds Classes with 2 those and should 3, in respectively Tables be 2located–4, except [38]. far that below tolbutamide the optimum and cinnarizine crystal growth were placedtemperature.The in different Classes Thus, 2 behavior and the 3, melt respectively of must Classes be [ 381first ].and cooled 2 compou to thends nucleation likely reflects temperature differences range in nucleation and then andheated crystalThe to di theff growtherent crystal behavior temperatures growth of temperature Classes (Figure 1 and for4). 2 compoundscrystalFor Classlization 1 compounds, likely to proceed. reflects the diHowever,ff erencesoptimum if in thenucleation nucleation cooling andrate crystalis sufficiently growthgrowth slow, temperaturestemperatures there is (Figurea shouldfinite4 chance). be For close Class for nucleationto 1 compounds,each other; to occur thehence, optimum at theafter optimum nucleationreaching crystal an and optimum crystalgrowth growthtemperature temperatures whereeven thoughboth should nucleation the be closenucleation toand each crystal rate other; isgr hence,owthvery low,proceed, after reachingwhich the couldmelt an optimum canexplain crystallize. temperaturethe similar This whereprocessclassifications both is expected nucleation produced to andbe by based crystal the two on growth methods.homogeneous proceed, the nucleation. melt can crystallize.In contrast, This the processoptimum is expectednucleation to betemperature based on homogeneousfor Class 2 compounds nucleation. should In contrast, be located the optimum far below nucleation the optimum temperature crystal for growth Class 2 compoundstemperature. should Thus, be the located melt farmust below be thefirst optimum cooled to crystal the nucleation growth temperature. temperature Thus, range the meltand mustthen beheated first cooledto the crystal to the nucleationgrowth temperature temperature for range crystal andlization then heatedto proceed. to the However, crystal growth if the temperaturecooling rate foris sufficiently crystallization slow, to there proceed. is a However,finite chance if the for cooling nucleation rate is to su occurfficiently at the slow, optimum there is crystal a finite growth chance fortemperature nucleation even to occur though at the the optimum nucleation crystal rate growth is very temperature low, which even thoughcould theexplain nucleation the similar rate is veryclassifications low, which produced could explain by the the two similar methods. classifications produced by the two methods.

Figure 4. Schematic representation of the temperature dependence of the nucleation and crystal growth temperatures for Classes 1 and 2 compounds.

Figure 4.4. SchematicSchematic representation representation of of the the temperature temperatur dependencee dependence of the of nucleation the nucleation and crystal and growthcrystal temperaturesgrowth temperatures for Classes for 1Cl andasses 2 compounds.1 and 2 compounds.

Pharmaceutics 2018, 10, x FOR PEER REVIEW 7 of 17

PharmaceuticsFigure2019 5 shows, 11, 202 reheating DSC curves of celecoxib melt, illustrating the dependence of the7 cold of 17 crystallization on the target temperature of the cooling process [43]. When the melt was cooled down to −20 °C, a crystallization exotherm was observed during the subsequent heating process. However,Figure no5 shows crystallization reheating was DSC observed curves of when celecoxib the melt,melt illustratingwas cooled the down dependence to 30 °C, of although the cold celecoxibcrystallization is known on the as target a Class temperature 2 compound. of theOur cooling investigation process revealed [43]. When that the the melt optimum was cooled nucleation down to 20 C, a crystallization exotherm was observed during the subsequent heating process. However, temperature− ◦ of celecoxib was ca. −50 °C; thus, cooling to 30 °C was obviously not enough for inducingno crystallization nucleation. was In observed the classi whenfication the meltcriteria was discussed cooled down above, to30 the◦C, minimum although temperature celecoxib is known of the coolingas a Class process 2 compound. is not specified. Our investigation However, revealeda poor understanding that the optimum of the nucleation nucleation temperature process may of celecoxib was ca. 50 C; thus, cooling to 30 C was obviously not enough for inducing nucleation. result in the misclassification− ◦ of a particular compound.◦ In theThe classification different behavior criteria discussedof Classes above, 2 and the3 compound minimums temperatureis likely due ofto thethe cooling different process strength is not of theirspecified. molecular However, interactions. a poor understanding Thus, the presence of the nucleationof neighboring process molecules may result during in the the misclassification crystallization cannotof a particular be ignored, compound. and the crystallization is based on heterogeneous nucleation.

Figure 5.5.Reheating Reheating DSC DSC curves curves of celecoxib of celecoxib melt, illustrating melt, illustrating the dependence the dependence of the cold crystallizationof the cold crystallizationon the target temperature on the target of temperature the cooling processof the cooling (shown process in thefigure). (shown in the figure).

3. RelationshipThe different between behavior Crystallization of Classes 2 and Tendency 3 compounds and Isothermal is likely due Crystallization to the different strength of their molecular interactions. Thus, the presence of neighboring molecules during the crystallization cannot The crystallization tendency discussed above does not directly correlate with the physical be ignored, and the crystallization is based on heterogeneous nucleation. stability under isothermal conditions. However, these two processes do have some indirect relationships.3. Relationship Figure between 6 shows Crystallization the time to Tendency reach 10% and crystallinity Isothermal Crystallization(t10, expressed in minutes) for pharmaceutical glasses as a function of Tg/T, where T is the storage temperature [44]. These data wereThe acquired crystallization for quenched tendency glass discussed pellets under above dry does conditions. not directly Crystallization correlate with has the physicalfrequently stability been observedunder isothermal to start at conditions. the surface However, [45,46]. Since these the two pellets processes have a do very have small some surface indirect area, relationships. the surface effectsFigure 6 onshows the thecrystallization time to reach were 10% almost crystallinity eliminated ( t10, expressed in this experiment. in minutes) forClearly, pharmaceutical the data correspondingglasses as a function to most of compoundsTg/T, where fellT is on the a storageuniversa temperaturel line; in particular, [44]. These the compounds data were acquired located foron quenchedthe line belonged glass pellets to underClasses dry 1conditions. and 2. The Crystallization other compounds, has frequently which beenexhibited observed better to start stability at the surface [45,46]. Since the pellets have a very small surface area, the surface effects on the crystallization especially above Tg, belonged to Class 3. wereThe almost above eliminated data were in this obtained experiment. by fitting Clearly, the the cr dataystallinity corresponding value at to each most time compounds point to fell the on Avrami–Erofeeva universal line; in equation. particular, The the ob compoundstained Avrami located exponents on the line are belonged shown toin ClassesTable 5 1 Smaller and 2. The Avrami other exponentscompounds, were which obtained exhibited for better higher stability classificatio especiallyn numbers, above T gwhich, belonged indicate to Classs that 3. the nucleation mechanismThe above becomes data more were homogeneous obtained by fittingwith decreasing the crystallinity classification value number. at each This time hypothesis point to the is Avrami–Erofeevalso supported equation.by a previous The obtained in-situ Avramianalysis exponents of the isothermal are shown crystallization in Table5 Smaller process Avrami of tolbutamideexponents were and acetaminophen obtained for higher using classificationsynchrotron X-ray numbers, diffraction which [44]. indicates that the nucleation mechanism becomes more homogeneous with decreasing classification number. This hypothesis is also supported by a previous in-situ analysis of the isothermal crystallization process of tolbutamide and acetaminophen using synchrotron X-ray diffraction [44].

Pharmaceutics 20192018,, 1110,, 202x FOR PEER REVIEW 88 of of 17

Figure 6. InitiationInitiation time time of of crystallization crystallization (t (10t,10 min), min) as asa function a function of ofTg/Tg. /TheT. The q and q and FD FDlabels labels in the in theparentheses parentheses indicate indicate that thatthe glass the glass was wasprepared prepared by quenching by quenching and andfreeze-dr freeze-drying,ying, respectively. respectively. The Thenumbers numbers in parentheses in parentheses denote denote the the crystallization crystallization tendency tendency classification. classification. The The universal universal line line is the best fit for Classes 1 and 2 compounds (ln(t10) = 66.2Tg∕/T 57.0). best fit for Classes 1 and 2 compounds (ln(10) = 66.2 − 57.0). Table 5. Ranges of Avrami exponents for isothermal crystallization. Table 5. Ranges of Avrami exponents for isothermal crystallization. Classification Compound Avrami Exponent Classification Compound Avrami Exponent TolbutamideTolbutamide 3.7–4.6 3.7–4.6 ClassClass 1 1 ChlorpropamideChlorpropamide 3.0–4.23.0–4.2 AcetaminophenAcetaminophen 2.1–3.0 2.1–3.0 ClassClass 2 2 NifedipineNifedipine 2.0 2.0 RitonavirRitonavir 2.2–3.1 2.2–3.1 IndomethacinIndomethacin 1.0–2.6 1.0–2.6 ClassClass 3 3 LoratadineLoratadine 1.1–1.5 1.1–1.5 ProbucolProbucol 1.2–1.3 1.2–1.3

The crystallizationcrystallization of of some some glasses glasses was observedwas observed to start atto thestart surface. at the In thesurface. case ofIn indomethacin, the case of crystallizationindomethacin, iscrystallization enhanced with is enhanced decreasing with particle decreasing size, which particle is most size, likelywhich due is most to the likely increasing due to surfacethe increasing area [45 ].surface Moreover, area the [45]. crystallization Moreover, ofthe indomethacin crystallization glass of particlesindomethacin is retarded glass by particles a polymer is coatingretarded of by the a polymer surface [ 46coating]. Quenched of the surface ritonavir [46]. glass Quenched exhibited ritonavir higher glass stability exhibited relative higher to that stability of the compoundsrelative to that located of the on compounds the universal located line inon Figure the universal6. However, line in the Figure stability 6. However, of freeze-dried the stability ritonavir of glassfreeze-dried could be ritonavir explained glass by thecould universal be explained line, which by isthe likely universal due to line, the increasewhich is in likely surface due area to [47the]. Theincrease lower in packingsurface area of the [47]. glass The structurelower packing might of also the partiallyglass structure contribute might to also eliminate partially the contribute effect of to eliminate the effect of molecular interactions. The surface effects are usually explained in terms of molecular interactions. The surface effects are usually explained in terms of the higher mobility of the higher mobility of surface molecules [48], due to a decreased number of nearest neighbor surface molecules [48], due to a decreased number of nearest neighbor molecules [49]. molecules [49]. The results in Figure6 suggest that the physical stability of Classes 1 and 2 compounds was The results in Figure 6 suggest that the physical stability of Classes 1 and 2 compounds was strongly affected by the temperature. In these cases, physical stabilization of the glasses appears strongly affected by the temperature. In these cases, physical stabilization of the glasses appears difficult to achieve without adding excipients. However, as the crystallization of Class 3 compounds difficult to achieve without adding excipients. However, as the crystallization of Class 3 is influenced by molecular interactions, physical stabilization of these systems may be achieved by compounds is influenced by molecular interactions, physical stabilization of these systems may be manipulating these interactions. In fact, quenched ritonavir glass had higher stability compared to achieved by manipulating these interactions. In fact, quenched ritonavir glass had higher stability that of the freeze-dried glass, as discussed above. compared to that of the freeze-dried glass, as discussed above. Sub-Tg annealing based on this strategy was found to be an effective strategy for stabilizing Sub-Tg annealing based on this strategy was found to be an effective strategy for stabilizing ritonavir glass [50]. For example, ritonavir glass annealed at 40 ◦C for two days was much more ritonavir glass [50]. For example, ritonavir glass annealed at 40 °C for two days was much more stable compared to fresh glass. The fresh glass reached a crystallinity of 58% after annealing at 60 °C

Pharmaceutics 2019, 11, 202 9 of 17 Pharmaceutics 2018, 10, x FOR PEER REVIEW 9 of 17 stablefor six compared days, whereas to fresh the glass. glass The pre-annealed fresh glass reachedat 40 °C areached crystallinity a crystallinity of 58% after of annealingonly 8% after at 60 the◦C forsame six annealing days, whereas procedure the glass at 60 pre-annealed °C. Structural at analysis 40 ◦C reached revealed a crystallinitya change in ofthe only packing 8% after volume the sameand hydrogen-bonding annealing procedure pattern at 60 during◦C. Structural the pre-anneal analysising revealed at 40 °C, a change which inwas the the packing most likely volume source and hydrogen-bondingof the stabilization. patternSuch pre-annealing during the pre-annealing strategy did atnot 40 work◦C, which for Classes was the 1 and most 2 compounds likely source [50]. of the stabilization. Such pre-annealing strategy did not work for Classes 1 and 2 compounds [50]. 4. Non-Ideal Crystallization of Practical Glasses 4. Non-Ideal Crystallization of Practical Glasses The discussion presented above is based on observation under well-defined conditions, where effectThe of discussionmechanical presented stress, moisture above is sorption, based on and observation surface area under were well-defined minimized. conditions, Crystallization where ebehaviorffect of mechanicalof practical stress,glasses, moisture especially sorption, in the andcase surfaceof powder area samples, were minimized. may not be Crystallization explained in behaviorsuch an ideal of practical manner. glasses, Glasses especially prepared in by the grinding case of powdertypically samples, exhibit lower may not stability be explained than the in intact such anones ideal most manner. likely because Glasses of prepared remaining by grindingnuclei and/or typically small exhibit crystals lower that stabilitycannot be than detected the intact by X-ray ones mostpowder likely diffraction. because of remainingIn the observation nuclei and /orof smallCrow crystalsley et thatal. cannot[51], becrystallization detected by X-raybehavior powder of diindomethacinffraction. In theglasses observation prepared of Crowleyby cryogenic et al. grinding [51], crystallization of various behavior crystal forms of indomethacin depended glasseson the preparedinitial crystal by cryogenic form used, grinding suggesting of various that the crystal ground forms glasses depended remembered on the their initial original crystal forms form used,even suggestingafter the grinding. that the groundIn their glassesstudy, rememberedthey also obse theirrved original significant forms differences even after thein the grinding. crystallization In their study,rates of they ground also observed and quenched significant glasses. differences Thus, alth in theough crystallization grinding is ratesa simple of ground process and to quenched prepare glasses.amorphous Thus, form although in a grindinglaboratory is ascale, simple it process is not to recommended prepare amorphous because form of in difficulty a laboratory in scale,transformation it is not recommended into the amorphous because state of in di ffia molecularculty in transformation level. into the amorphous state in a molecularEven level.for melt–quenched glasses, application of subsequent grinding process can accelerate crystallizationEven for melt–quenched[52]. Moreover, glasses,very weak application stresses ofsuch subsequent as crack grindingformation process [53] and can transfer accelerate to crystallizationdifferent vessels [52 ].[52] Moreover, are also very suspected weak stresses as caus suches of as nucleation. crack formation Figure [53 ]7 and shows transfer comparison to different of vesselscrystallization [52] are behavior also suspected of melt–quenched as causes of nucleation.indomethacin Figure glasses7 shows at 30 comparison °C with or ofwithout crystallization grinding behaviorprocess before of melt–quenched the storage. indomethacinIn the absence glasses of the atgrinding 30 ◦C with process, or without the quenched grinding glass process remained before thecompletely storage. in In an the amorphous absence of state the for grinding more process,than one themonth. quenched However, glass if remained the grinding completely process inis anapplied amorphous for the statemelt–quenched for more than glass, one crystallization month. However, is initiated if the grinding within one process day. isThis applied comparison for the melt–quenchedclearly indicates glass, significant crystallization effect of isthe initiated grinding within process one day.on the This crystallization comparison clearlybehavior, indicates which significantappeared to eff beect due of theto increase grinding in process the surface on the area crystallization and mechanical behavior, stress. which It is also appeared interesting to be to due note to increasethat the crystal in the surfaceform obtained area and was mechanical not identical stress. in Itthese is also examples. interesting Since to noteno relevance that the crystalbetween form the obtainedpreparation was process not identical and crystal in these form examples. could be Since found, no relevance it might be between because the of preparation difference processin impurity and crystalprofiles. form could be found, it might be because of difference in impurity profiles.

Figure 7. IsothermalIsothermal crystallization crystallization of ofindomethacin indomethacin glasses glasses at 30 at °C 30 under◦C under dried dried condition. condition. (■) (Quenched) Quenched and and ground ground for for6 6min. min. Crystallized Crystallized to toform form γ γ[51].[51]. (◇ ( ) )Quenched Quenched and and ground. Crystallized to form form αα exceptexcept that that symbols symbols with with asterisk asterisk involves involves small small 3amount amount of form of form γ [54].γ [(54●].) (Quenched) Quenched and and cryoground. cryoground. Crystallized Crystallized to mixture to mixture of ofform form α αandand γ γ(our(our data). data). (▲ (N)) Quenched. Crystallized to form γ [[55].55]. ( ○)) QuenchedQuenched andand storedstored inin DSCDSC panpan (our(our data).data). CrystallizedCrystallized toto formform α whichwhich containscontains smallsmall amountamount# ofof formform γγ..

Crystallization of nifedipine is very sensitive to various factors including moisture sorption and mechanical stress. Thus, extensive care is required to investigate the ideal crystallization behavior as presented in Figure 6. In our experiments, crystalline powder was dried in a vacuum

Pharmaceutics 2019, 11, 202 10 of 17

Crystallization of nifedipine is very sensitive to various factors including moisture sorption and mechanicalPharmaceutics 2018 stress., 10, x Thus, FOR PEER extensive REVIEW care is required to investigate the ideal crystallization behavior 10 of as 17 presented in Figure6. In our experiments, crystalline powder was dried in a vacuum oven at 50 ◦C and storedoven at in 50 a desiccator°C and stored with silicain a desiccator gel before use.with Then, silica thegel dried before powder use. Then, was loadedthe dried in a powder hermetically was sealedloaded pan in a under hermetically flow of dried sealed nitrogen pan under air, and flow subjected of dried to nitrogen the melt–quench air, and proceduresubjected totoinitiate the melt– the stabilityquench procedure study. Only to after initiate such the careful stability treatment, study. theOnly data after which such could careful be explainedtreatment, bythe the data universal which linecould were be explained obtained. by the universal line were obtained. Therefore, the data for nifedipinenifedipine crystallizationcrystallization found in literature are usually faster than the expectation from the universaluniversal line.line. Figure 88 shows shows onsetonset crystallizationcrystallization timetime ofof nifedipinenifedipine glassesglasses extracted from variousvarious literatureliterature sources.sources. As As alre alreadyady presented in Figure 66,, thethe nifedipinenifedipine datadata obtained afterafter the the careful careful treatment treatment mentioned mentioned above above were explainablewere explainable by the universalby the universal line. However, line. theHowever, crystallization the crystallization was much fasterwas much for the faster glasses for loaded the glasses in normal loaded sealed in normal pans without sealed pans pretreatment. without Observationpretreatment. using Observation polarized using light microscopypolarized light by Bhugra microscopy et al. wasby Bhugra done in aet very al. was careful done manner in a very [56], wherecareful cracked manner glasses [56], where were eliminated cracked glasses from the were analysis, eliminated because from it can the enhance analysis, the because crystallization. it can However,enhance the the crystallization. crystallization However, was much the faster, crystallization presumably was because much the faster, glasses presumably could not because be shielded the fromglasses outer could atmosphere not be shielded completely. from outer atmosphere completely.

Figure 8.8. Onset crystallization time time ( ttoo,, min) min) of of nifedipine nifedipine gl glassass as as a a function function of of TTgg/T/T. .((■) AfterAfter thethe pretreatment (see text), quenched in hermeticallyhermetically sealed pan (our data) [[44].44]. (○)) QuenchedQuenched inin sealedsealed DSC panpan withoutwithout pretreatment pretreatment (our (our data). data). ( ()● Quenched) Quenched in DSC in DSC pan pan [57]. [57]. (N) Quenched (#▲) Quenched on glass on slidesglass andslides crystallization and crystallization was observed was observed by polarized by polari lightzed microscopy light microscopy [56]. Cracked [56]. glassesCracked were glasses excluded were fromexcluded the analysis. from the ( analysis.) Quenched (◆) inQuenched DSC pan in [58 DSC]. All pan the [58]. literature All the data literature were recalculated data were recalculated using the Tg valueusing ofthe 45.5 Tg ◦valueC. Definition of 45.5 of°C. onset Definition crystallization of onset time,crystallization which is analogous time, which to t 10is ,analogous is slightly ditoff erentt10, is dependingslightly different on literature, depending but itson impactliterature, is ignorable but its impact in the is analysis ignorable here. in the analysis here.

Compression process is alsoalso recognizedrecognized toto aaffeffectct thethe crystallizationcrystallization kinetics.kinetics. Figure9 9 shows shows eeffectffect ofof compressioncompression pressurepressure onon crystallizationcrystallization ofof sucrosesucrose glassglass investigatedinvestigated byby isothermalisothermal microcalorimetry [59[59].]. Initiation Initiation time time for crystallizationfor crystallization was rarelywas rarely influenced influenced below 0.5below MPa; 0.5 however, MPa; crystalhowever, growth crystal was growth enhanced was withenhanced increasing with pressure.increasing Itpressure. was shortened It was atshortened 2.5 MPa, at suggesting 2.5 MPa, thatsuggesting condensation that condensation of glass structure of glass can structure enhance nucleationcan enhance after nucleation application after of suchapplication relatively of weaksuch compressionrelatively weak force. compression Similarly, Ayenew force. etSimilarly, al. reported Ayen thatew cold et al. crystallization reported that of indomethacincold crystallization glass was of enhancedindomethacin by compression glass was at ca.enhanced 43.7 MPa by [60 compression]. In their study, atuncompressed ca. 43.7 MPa glass, [60]. which In wastheir prepared study, byuncompressed cooling the melt glass, at 0.2which◦C/min, was was prepared observed by tocool crystallizeing the atmelt 121.4 at◦ C0.2 during °C/min, subsequent was observed reheating to atcrystallize 5 ◦C/min. at However, 121.4 °C itduring decreased subsequent to 114.1, reheating 113.1, and at 112.7 5 °C/min.◦C, if theHowever, compression it decreased was applied to 114.1, for 1113.1, s, 2.5 and min, 112.7 or 5 min,°C, if respectively. the compression Rams-Baron was applied et al. observedfor 1 s, 2.5 that min, isothermal or 5 min, crystallization respectively. of etoricoxibRams-Baron was et significantlyal. observed enhancedthat isothermal after compression crystallization at 300of etoricoxib MPa; however, was significantly it could be preventedenhanced byafter mixing compression with polyvinylpyrroridone at 300 MPa; (PVP),however, where it investigationscould be prevented were done underby mixing the identical with polyvinylpyrroridone (PVP), where investigations were done under the identical relaxation time conditions [61]. This result indicated that physical barrier by excipients were very effective for inhibiting pressure-induced nucleation.

Pharmaceutics 2019, 11, 202 11 of 17 relaxation time conditions [61]. This result indicated that physical barrier by excipients were very effective for inhibiting pressure-induced nucleation. Based on the universal line, the only requirement for assuring three-year stability of pharmaceutical glasses at 25 ◦C is the Tg higher than 48 ◦C[44]. Its applicability to practical glasses which are produced underPharmaceutics various 2018 mechanical, 10, x FOR PEER stresses REVIEW without protection from outer atmosphere is discussed next. 11 of 17

Figure 9. EffectEffect of of compression compression pressure pressure on on crystallization heat heat flow flow curves of sucrose glassesglasses investigated byby isothermal isothermal microcalorimetry microcalorimetry (30 ◦(30C). Freeze-dried°C). Freeze-dried sucrose sucrose was compressed was compressed at pressure at ofpressure ca. 2.5 MPaof ca. (black), 2.5 MPa 0.5 MPa(black), (red), 0.5 or MPa 0.1 MPa(red), (blue) or 0.1 for MPa 10 s and(blue) subjected for 10 tos and the measurement.subjected to the measurement. 5. Relevance to Formulation Research PracticalBased on ASDs the cannotuniversal be manufacturedline, the only by requirement the melt–quenching for assuring procedure. three-year The crystallization stability of tendencypharmaceutical during glasses practical at formulation25 °C is the processesTg higher isthan also 48 of °C great [44]. interest Its applicability to formulators. to practical This is glasses similar butwhich diff areerent produced phenomena under from various the crystallization mechanical stresses from the without melt; therefore, protection some from attempts outer atmosphere have been madeis discussed to find next. relevance between them. The tendency to crystallize from solution after drying is of great importance for evaluating applicability of spray-drying. Eerdenbrugh et al. investigated the crystallization5. Relevance to of Formulation 51 compounds Research after removal of the solvent by spin coating, in order to identify possiblePractical correlations ASDs cannot between be manufactured the crystallization by the tendencies melt–quenching evaluated procedure. by thermal The analysiscrystallization upon coolingtendency/reheating during practical and during formulation drying from processes solutions is also [62]. of In great their interest analysis, to theformulators. compounds This that is exhibitedsimilar but a tendencydifferent phenomena to crystallize from immediately the crystalliz afteration spin from coating the weremelt; denotedtherefore, as some Class attempts 1, those thathave crystallized been made withinto find one relevance week were between categorized them. Th ase Class tendency 2, and to the crystallize remaining from compounds solution wereafter regardeddrying is asof Class great 3. importance Approximately for evaluating 76% of the applicability compounds classifiedof spray-drying. as Class 1Eerdenbrugh by DSC were et also al. assignedinvestigated to Class the 1crystallization by the spin coating of 51 method,compounds whereas after 76% removal of the of compounds the solvent classified by spin as coating, Class 3 byin DSCorder were to identify again classified possible incorrelations the same groupbetween by thethe spincrystallization coating approach. tendencies The evaluatedTg values by seemed thermal to breakanalysis the upon correlation cooling/reheating between the twoand classification during dryi methods.ng from solutions [62]. In their analysis, the compoundsThe relevance that exhibited to vitrification a tendency during to crystalliz millinge has immediately also been studied.after spin Blaabjergcoating were et al. denoted reported as minimumClass 1, those milling that times crystallized to achieve within vitrification one week as were 90 and categorized 270 min for as ClassesClass 2, 3 and and the 2 compounds, remaining respectively,compounds whereaswere regarded no vitrification as Class was 3. Approximately achieved for any 76% of theof the Class compounds 1 compounds classified [42]. It as should Class be 1 notedby DSC that were some also Classes assigned 2 and to Class 3 compounds 1 by the failedspin coating to form method, amorphous whereas systems, 76% mostof the likely compounds due to theirclassified low Tasg. Class This observation3 by DSC were suggests again that classified the crystallization in the same tendency group by from the spin the melt coating can beapproach. used to guideThe Tg the values design seemed of hot-melt to break extrusion the correlation processes, between along the with two additional classification information methods. on the Tg values. Thus,The relevance applicability to vitrification of ASD technology during milling to poorly has solublealso been candidates studied. mayBlaabjerg be judged et al. fromreported the crystallizationminimum milling tendency times to determined achieve vitrification by DSC withas 90 theand information 270 min for onClassesTg. In3 and the 2 formulations, compounds, polymericrespectively, excipients whereas no are vitrification used for twowas achieved purposes: for physical any of the stabilization Class 1 compounds and improvement [42]. It should of dissolutionbe noted that/supersaturation some Classes 2 behaviors and 3 compounds [12]. Class fail 3ed compounds to form amorphous can be expected systems, to bemost transformed likely due intoto their the amorphouslow Tg. This state observation using typical suggests formulation that the processes crystallization for ASDs tendency even without from excipients.the melt can Main be purposesused to guide of addition the design of polymeric of hot-melt excipients extrusion in pr theocesses, ASD design along with are to additional raise Tg for information ensuring storage on the stabilityTg values. and to improve dissolution behavior. Amount of excipient may be kept small for these compounds.Thus, applicability Even if amount of ASD of the technology drug exceeds to solidpoorly solubility soluble limit,candidates the drug may is expected be judged to remainfrom the in thecrystallization amorphous statetendency [63]. Indetermined contrast, Class by DSC 1 compounds with the must information be completely on T mixedg. In the with formulations, excipients in polymeric excipients are used for two purposes: physical stabilization and improvement of dissolution/supersaturation behaviors [12]. Class 3 compounds can be expected to be transformed into the amorphous state using typical formulation processes for ASDs even without excipients. Main purposes of addition of polymeric excipients in the ASD design are to raise Tg for ensuring storage stability and to improve dissolution behavior. Amount of excipient may be kept small for these compounds. Even if amount of the drug exceeds solid solubility limit, the drug is expected to remain in the amorphous state [63]. In contrast, Class 1 compounds must be completely mixed with excipients in a molecular level for the successful transformation to the amorphous state. The

Pharmaceutics 2019, 11, 202 12 of 17 Pharmaceutics 2018, 10, x FOR PEER REVIEW 12 of 17 amountsa molecular of excipients level for the are successful expected transformationto be larger compared to the amorphous to that for state. Class The 3 compounds. amounts of Typically, excipients solidare expected solubility to beof drug larger in compared polymeric to matrix that for un Classder 3ambient compounds. temperature Typically, is below solid solubility 30%, sometimes of drug belowin polymeric 10%, depending matrix under on ambientcombination temperature of drug is and below excipient 30%, sometimes [21–23]. Moreover, below 10%, it dependingis frequently on observedcombination that of drugthe effective and excipient polymer [21–23 for]. Moreover,physical itstabilization is frequently and observed dissolution that the eimprovementffective polymer is different.for physical Hydroxypropyl stabilization and methylce dissolutionllulose improvement acetate succinate is different. frequently Hydroxypropyl offers great methylcellulose effect for maintainingacetate succinate high frequently level of supersaturation; offers great effect forhowever, maintaining its miscibility high level with of supersaturation; drug is typically however, low. itsIn contrast,miscibility PVP with and drug its is derivatives typically low. have In contrast,relatively PVP high and miscibility its derivatives with havedrug, relatively but its supersaturation high miscibility effectwith drug, cannot but be its maintained supersaturation for long effect duration cannot be in maintained many cases. for It long must duration be recognized in many cases.as well It mustthat preparedbe recognized ASDs as are well not that necessarily prepared in ASDsthe equilibrium are not necessarily state. If ASDs in the are equilibrium prepared under state. an If ASDselevated are temperatureprepared under condition, an elevated as in temperature case of hot-melt condition, extrusion, as in casethe mixing of hot-melt state extrusion, at this temperature the mixing may state be at kineticallythis temperature frozen may even be kineticallyafter cooling frozen to evenambien aftert coolingtemperature. to ambient In spray-drying, temperature. Inthe spray-drying, drug and excipientthe drug andmolecules excipient may molecules be separated may be based separated on the based difference on the in di fftheirerence mole in theircular molecular weights, because weights, diffusionbecause dirateffusion during rate evaporation during evaporation process is process different is di[64,65].fferent This [64, 65kinetically-separated]. This kinetically-separated structure maystructure also maybe frozen also be after frozen the after drying the [65,66]. drying [65If ,so66lvents]. If solvents are used are during used during the preparation, the preparation, as in as the in casesthe cases of spray-drying of spray-drying and and coprecipitation, coprecipitation, the the mixi mixingng state state of ofthe the ASDs ASDs is is affected affected by by the the solvent speciesspecies [67]. [67]. In In such such cases, cases, the the mixing mixing state state may may change change with with time time [23]. [23]. How the universal line line in in Figure Figure 66 isis applicableapplicable toto multi-componentmulti-component ASDs is of great interest. Figure 10 shows comparison of the onset crystallization time of single phase ASDs appearing in the literature.literature. AsAs anan overall overall trend, trend, the the universal universal line line seems seems to work to work even foreven the for multicomponent the multicomponent systems. systems.Comparison Comparison of nifedipine of nifedipine/PVP/PVP ASDs from ASDs three fr diomfferent three stuides different implies stuides that millingimplies enhancesthat milling the enhancesnucleation. the However,nucleation. presence However, of polymericpresence of excipients polymeric appears excipients to stabilizeappears to the stabilize ASDsmore the ASDs than moreexpected than from expected change from in Tchangeg (i.e., molecularin Tg (i.e., mobility),molecular mostmobility), likely most because likely of because dilution of e ffdilutionect and effectinteraction and interaction with drug. with The drug. result The for result Sanofi–Aventis for Sanofi–Aventis compounds compounds is the most is the informative most informative from a frompractical a practical point of point view, becauseof view, the because ASD was the preparedASD was by prepared spray-drying. by spray-drying. Stability of this Stability ASD is of a littlethis ASDlower is but a little roughly lower agrees but withroughly the universalagrees with line the regardless universal of absenceline regardless/presence of of absence/presence the moisture. When of theeach moisture. dataset is When fitted witheach adataset regression is fitted line, theirwith slopesa regression are almost line, the their same, slop suggestinges are almost that the activation same, suggestingenergy for nucleationthat activation does notenergy significantly for nucleation depend does on thenot type significantly of ASDs. depend Design of on accelerated the type of physical ASDs. Designstability of test accelerated may be possible physical for stability ASDs basedtest may on be this possible information. for ASDs based on this information.

Figure 10. 10. OnsetOnset crystallization crystallization time time(to, min) (to, of min) various of various ASDs as ASDs a function as a of function Tg/T. (◆ of,◆T,◇g/T) . Nifedipine/PVP( , , ) Nifedipine ASDs/PVP prepared ASDs by prepared melt–quench by melt–quench[68,69] followed [68 by,69 milling] followed [58], respectively. by milling [(58●],, ●respectively.) Phenobarbital/PVP3 (, ) Phenobarbital ASDs /PVPprepar ASDsed preparedby melt–quench by melt–quench [68,69]. [68 ,69(▲].,△ (N), )Sanofi–Aventis Sanofi–Aventis 4 compound/HPMCPcompound/HPMCP ASDs ASDs prepared prepared by by spray-drying spray-drying stored stored under under dried dried and and humid humid conditions, conditions,

respectivelyrespectively [[70].70]. DefinitionDefinition of of onset onset crystallization crystallization time, time, which which is analogous is analogous to t10, isto slightly t10, is dislightlyfferent differentdepending depending on the study, on the but itsstudy, impact but is its ignorable impact inis theignorable analysis in here. the HPMCP,analysis Hydroxypropylhere. HPMCP, Hydroxypropylmethylcellulose methylcellulose phthalate. phthalate.

Pharmaceutics 2019, 11, 202 13 of 17

6. Relevance to the Dissolution Benefits of ASDs The greatest advantage of ASDs is that they can achieve supersaturation of poorly soluble drugs. Supersaturation can be maintained unless crystallization occurs in aqueous environments [71]. Thus, it is important to understand the controlling factors that cause crystallization of pharmaceutical glasses in aqueous media. Our preliminary investigation revealed that crystallization proceeds immediately above Tg of the solid [33]. Blaabjerg et al. reported that the degree of supersaturation tended to be high for good glass formers, but no correlation was found between crystallization tendency and supersaturation lifetime [72]. We have shown that amount of orally absorbed fenofibrate was correlated with liquid–liquid phase separation concentration, which is analogous to degree of supersaturation, if the oral absorption was limited by solubility [13]. Thus, suppression of the crystallization tendency can be an option of chemical modification of the poorly soluble candidates instead of increasing aqueous solubility. Alhalaweh analyzed the relationship between the crystallization tendencies from the melt and those in solution, highlighting the need to consider structural factors to improve the correlation between these tendencies [73]. From the viewpoints of physical stability and supersaturation ability, Class 3 compounds seem to be suitable candidates for ASDs. In fact, most of the marketed ASDs consist of Class 3 compounds [74].

7. Summary This review provides the classification of the crystallization tendencies of pharmaceutical compounds, focusing on its relevance for the glass properties. Possible relationships discussed in this review are summarized in Table6. In addition to its e ffectiveness for describing the physical stabilities of ASDs, this classification provides important insights into the glass properties. The investigation of the crystallization mechanism of small organic compounds is an attractive subject because of their structural diversity and complicated molecular interactions, in contrast to the inorganic compounds that have dominated the field of glass science so far. Further progress in this field can make a significant contribution to both basic glass science and practical developmental studies of pharmaceutical products.

Table 6. Relevance of crystallization tendency classification for glass properties.

With increasing classification number: Nucleation becomes more heterogeneous • The nucleation barrier becomes larger • Surface effects become more important • Vitrification during the formulation processes may become easier • The supersaturation ability may increase • The universal line in Figure6 is applicable for Class 1 and 2 compounds, whereas the stability of Class 3 • compounds may be better Stabilization may be achieved via thermal treatment •

Preparation of practical formulations involves some procedure to enhance nucleation. Ideality of the nucleation/crystallization behavior is destroyed by application of some activation processes such as milling. However, presence of polymeric excipients can contribute to stabilization, presumably due to dilution effect and its interaction with drug molecules. As a result, deviation from the ideal behavior due to formulation processes is suppressed for enabling rough prediction of the crystallization time. Design of accelerated physical stability test may be possible for ASDs based on this observation. Although compounds in any classes can be formulated as ASDs, Class 3 compounds obviously have the highest applicability. In addition to their high physical stability, they may have an advantage in supersaturation ability that has great contribution to enhanced absorption. Therefore, chemical modification to decrease crystallization tendency may be considered as an option for drug design instead of increasing solubility. Pharmaceutics 2019, 11, 202 14 of 17

Funding: This research received no external funding. Conflicts of Interest: The author declares no conflicts of interest.

References

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