Instrumental Analytical Techniques for the Characterization of Crystals

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Instrumental Analytical Techniques for the Characterization of Crystals in Pharmaceutics and Foods Yiqun Qiao, Ruirui Qiao, Yuning He, Cuiping Shi, Yao Liu, Hongxun Hao, Jing Su, and Jian Zhong Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b00759 • Publication Date (Web): 25 Sep 2017 Downloaded from http://pubs.acs.org on September 30, 2017

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Crystal Growth & Design

Instrumental Analytical Techniques for the Characterization of Crystals in Pharmaceutics and Foods Yiqun Qiao,1, # Ruirui Qiao,2, # Yuning He,1 Cuiping Shi,1 Yao Liu,3 Hongxun Hao,4,* Jing Su,5,* Jian Zhong1,* 1

Laboratory of Quality and Safety Risk Assessment for Aquatic Products on Storage and

Preservation (Shanghai), Ministry of Agriculture, Shanghai Engineering Research Center of Aquatic-Product Processing and Preservation, College of Food Science & Technology, Shanghai Ocean University, Shanghai 201306, China 2

ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash

Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia 3

Department of Cancer Biology, Dana−Farber Cancer Institute, Harvard Medical School,

Boston, Massachusetts 02215, United States 4

State Key Laboratory of Chemical Engineering, Collaborative Innovation Center of

Chemical Science and Chemical Engineering (Tianjin), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China 5

School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China

#

These authors contributed equally to this work.

Corresponding authors: [email protected] (Prof. Jian Zhong), [email protected] (Prof. Jing Su), or E-mail: [email protected] (Prof. Hongxun Hao)

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Abstract: Crystallization has attracted more and more attentions from the scientists and engineers in the field of pharmaceutics and foods. In order to understand the crystals, many instrumental analytical techniques have been developed and applied in this field. In this work, recent application progress of instrumental analytical techniques for the characterization of crystal forms in pharmaceutics and foods has been reviewed and discussed. These techniques include X-ray diffraction, thermal analytical techniques, molecular vibrational spectroscopy, microscopy observation techniques, solid-state nuclear magnetic resonance spectroscopy, nuclear quadrupole resonance spectroscopy, and etc. This work will provide a comprehensive guide to scientists and engineers in this field to characterize crystals in pharmaceutics and foods.

Keywords: instrumental analytical techniques; crystals; pharmaceutics; food


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1.

Introduction Crystal structures mean the ordered arrangement of atoms, ions or molecules in a

material. A crystalline solid is a type of materials whose atoms, ions, or molecules are in crystal structures. Crystallization is a natural or artificial process where a solid crystalline forms. It is well known that most of the drugs and many kinds of food materials are crystalline solids.1-2 Therefore, crystallization have attracted more and more attentions from the scientists and engineers in the field of pharmaceutics and foods.3-4 The forms of a given solid drug or food substance may be classified into four types:5 (1) polymorphs. These are forms with the same chemicals but different crystal structures; (2) solvates. These are forms that contain solvent molecules in the crystal structure; (3) desolvated solvates. These are forms that the solvent molecules are removed from solvates and the original crystal structures are still retained. (4) amorphous forms that are solid without crystal structures. Most organic and inorganic compounds in pharmaceutics and food additives can exist in one or more crystalline forms.6 Solid cystallines can be classified into polymorphs, solvates, and desolvated solvates. Polymorphs can be classified into conformational polymorphs, configurational polymorphs, color polymorphs and pseudo polymorphs. Different crystalline forms have different crystal packing, and/or molecular conformation, and lattice energy and entropy. Hence, different crystallines of a given solid drug or food substance may show different physical properties including appearances, hardness, color, solubility, melting point, dissolution, and etc. Further, it is essential to control and/or maintain the crystal forms during the processing because any change of the crystal forms can change the the stability, bioavailability, and efficacy of the final products.7 A full evaluation of possible variations in crystallines is important for the research and development of new drugs and food additives. Recently, the US Food and Drug Administration (FDA) recognized the



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importance of crystal structures and stated appropriate analytical procedures are needed to be used in drug guidelines to detect drug crystal forms. There are a lot of instrumental analytical techniques for the characterization of crystal forms in pharmaceutics and foods, such as X-ray diffraction (XRD), infrared and Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), optical and electroscopy, and atomic force microscopy (AFM). These techniques are generally based on the different physicochemical properties of different crystalline solids. Only few reviews have been published to dissucss analytical techniques of the crystals in pharmaceutics and foods. Typical reviews include the summary of spectral methods,8 quantitative techniques,9 comprehensive analytical techniques from molecular determination to crystal characterization for one substance,10 and one type of analystical techniques.11-12 The interested readers may read these reviews for detail. These reviews have not comprehensively summarized the instrumental analytical techniques for the crystal characterization in pharmaceutics and foods. In this review, we will comprehensively summarize and discuss the application of the common instrumental analytical techniques for the characterization of crystal structures in pharmaceutics and foods (Figure 1): X-ray diffraction methods, thermal analytical techniques, molecular vibrational spectroscopy methods, microscopy observation techniques, solid-state nuclear magnetic resonance spectroscopy, nuclear quadrupole resonance spectroscopy, and etc. 2. Instrumental analytical techniques for the characterization of crystals in pharmaceutics and foods 2.1. X-ray diffraction XRD is the most classic and reliable way to analyze the crystalline forms. It can be used to distinguish crystalline state from amorphous state, to identify different crystal varieties, to analyze mixtures from compounds, to determine the crystal structure of a crystal material, to determine lattice parameters (such as the distance between atoms, ring plane-ring plane 4 ACS Paragon Plus Environment

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distance, and dihedral angle), as well as to compare the difference between different crystal forms. XRD methods can be divided into two kinds: powder X-ray diffraction (PXRD) and single crystal X-ray diffraction (SCXRD). The forth is mainly used for the identification and purity test of crystalline materials, while the latter is mainly used for the determination of the molecular weights and crystal structures. 2.1.1. Powder X-ray diffraction PXRD is one of the most common methods for the study of crystalline forms.11 The sample can be not a single crystal but a sum of a large number of randomly oriented crystals. This method is simple and rapid to analyze the crystal structures of a material. Like a fingerprint of human being, the XRD pattern of every crystal can be applied to analyze the crystal form change, crystallinity, state of crystal structure, and the presence of mixed crystal or not. Generally, the particle size of the powder sample should be less than 44 µm for qualitative analysis and be less than 10 µm for quantitative analysis. It should be noted it is necessary to prevent the crystal structure change during the sample preparation process such as the grinding and screening processes. PXRD has been widely applied in the field of the pharmaceutical and food. Chao Hong et al.13 determine PXRD patterns of active pharmaceutical ingredient (myricetin), four cocrystal coformers (caffeine, nicotinamide, isonicotinamide, and 4-cyanopyridine), and their cocrystals. The PXRD patterns showed that the four cocrystals clearly differed from the individual myricetin and cocrystal coformers. Compared with the individual myricetin and cocrystal coformers, the cocrystals had some new characteristic reflections but did not have some characteristic reflections. It proved the formation of cocrystals (the new eutectic phase) and the cocrystals are not simple mixed between these individual myricetin and cocrystal coformers. Therefore, PXRD is beneficial for the development and application of the cocrystallization technology in drug delivery. Keswani et al.14 used PXRD to analyze the 5 ACS Paragon Plus Environment


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crystal structures of crystal-like drug inclusions (CLDIs) formed by clofazimine, a weakly basic lipophilic drug. The isolated CLDIs from the spleens of clofazimine-treated mice had common peaks not to commercial clofazimine but to clofazimine crystals formed in HCl or NH4Cl (pH4-5). It suggested that the intracellular chloride transport mechanisms might play a pivotal role in the formation of CLDIs in vivo. This work proved that PXRD can be applied to analyze the crystal formation mechanism in vivo by comparing the spectra of the in vivo crystals with different crystals that were formed in different in vitro conditions. Delacharlerie et al.15 used PXRD to investigate the effect of lecithins on the polymorphism of the crystallized blends (70% palm oil e 30% rapeseed oil) and found native lecithin promoted the β′ to β polymorphic transition. It proved PXRD is a simple method to analyze the effect of components on the crystal structures of complex systems. Miclaus et al.16 used PXRD to identify other quercetin crystalline forms besides the major dihydrate form in two commercial quercetin dietary supplements, which are complex mixtures of active ingredient(s) and excipients (5-7 components) (Figure 2). By combining PXRD patterns with solid state nuclear magnetic resonance, another two solid forms of tiny amounts were also identified. This work proved that PXRD can be applied to analyze the crystalline forms of tiny amount in the measured sample. In order to correlate unambiguously thermal change to structural changes, Schammé et al.17 used integrated temperature resolved PXRD-DSC system to study the behaviours of stable Form I and metastable Form II of an amorphous mouth and throat drug namely Biclotymol as a function of temperature. PXRD and DSC results showed an good agreement at the same characteristic temperatures. Therefore, the simultaneous application of different instrumental analytical techniques for a sample is powerful for crystal structure research. 2.1.2. Single crystal X-ray diffraction It is well known that single crystal X-ray diffraction (SCRXD) is the most reliable method to confirm the presence of polycrystalline forms in a sample. SCXRD can be applied 6 ACS Paragon Plus Environment

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to analyze the crystal lattice parameters, and then to identify the crystalline configuration and molecular arrangements. This method can also be used to measure the crystal water/solvent and to identify the bonding relationship between the basic group and the acid radical of saltforming drugs. Sufficient size and high purity are required for the SCRXD analysis. However, it is difficult to obtain a single crystal with sufficient size and high purity for many drugs and foods, which has limited the application of this method.18 SCXRD has been widely applied in the field of the pharmaceutical and food. Yan et al.19 used both PXRD and SCXRD to characterize the cocrystal system of pimelic acid with poorly soluble melatonin. Cocrystal was identified by the appearance of new peaks in the diffractogram of PXRD. Then the cocrystals were analyzed by SCXRD to identify the molecular interactions between pimelic acid and melatonin. From the obtained crystallographic data and hydrogen bond parameters, the crystal structures could be proposed, as shown in Figure 3. This work proved SCXRD is useful to analyze the the molecular interactions including molecular distance and bonds in cocrystals. Rauf et al.20 used SCXRD to determine the crystal structures of a series of N,N,N′-trisubstituted thioureas and their Ni(II) complexes. The results indicated that all the complexes had square planar geometry. Moreover, the N,N,N′-trisubstituted thioureas showed bidentate mode of coordination at nickel centre through oxygen and sulfur atoms. Sarkar et al.21 prepared molecular salts and cocrystals of anti-depressant drug mirtazapine and then used SCXRD to determine the crystal structures of tartarate and oxalate molecular salts. Sanphui et al.22 prepared cocrystals of an antifungal drug voriconazole with biologically safe coformers and salts of voriconazole with hydrochloric acid and oxalic acid. The application of SCXRD confirmed the presence (salt) or absence (cocrystal) of proton transfer in these multicomponent crystals. Shiju et al.23 synthesized Schiff base-platinum(II) complexes and used SCXRD to determine their crystal structures, which verified the Schiff base ligand L5's structure. Rizvi et al.24 synthesized a new pharmacophore organoselenium compound and used SCXRD to determine its crystal 7 ACS Paragon Plus Environment


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structure. The SCXRD results demonstrated the compound crystallized in a triclinic crystal system with P-1 space group. Further, the unit cell parameters and the perspective view of the Oak Ridge thermal ellipsoid plot (ORTEP) diagram were obtained. These works demonstrated SCXRD is an excellent tool to characterize the crystal structures of both single crystal and cocrystal, especially the molecular interactions in cocrystal. 2.2. Thermal analytical techniques Different crystal forms have different heat absorption/release behaviours during their heating/cooling process. Thermal analysis is to analyze the relationship between the physicochemical properties and temperature by controlling the temperature change. The produced thermal analysis curves can be applied to judge the similarities and differences of crystal forms of different drug/food crystals. There are three main thermal analysis methods: differential scanning calorimetry (DSC),25 differential thermal analysis (DTA),26 and thermogravimetric analysis (TGA).27 2.2.1. Differential scanning calorimeter DSC is a thermoanalytical technique to measure the energy difference between the sample and the inert reference (generally α-Al2O3) as a function of temperature. Both the sample and reference are maintained at nearly the same temperature throughout the experiment. This technique was developed by Watson and O’Neill in 1962 and was commercialized in 1963.28 The principle of this technique is that compared with the inert reference, the sample requires more or less heat when the sample undergoes a physical transformation such as phase transitions. It can be applied to the observed fusion and crystallization events as well as glass transition temperature. It also can be applied for studies of oxidation and other chemical reactions. It should be noted that high speed (hyper) DSC,29 modulated DSC,30 and high pressure DSC31 has been developed and applied for the studies of drug/food crystals. DSC has been widely applied for studies of drug/food crystals. Zuo et al.32 used DSC to 8 ACS Paragon Plus Environment

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study the changes of crystalline structure and characteristic of native starch which had been esterified and modified (Figure 4). The DSC gelatinization temperature of esterified starch shifted to low temperature, which demonstrated that esterification modification changed the crystalline structure and crystallinity degree of native starch. It proved that DSC is an excellent tool to differentiate modified food crystals with un-modified food crystals. Lv et al.33 used DSC to study the effects of hydroxyapatite nanoparticles on the devitrification and recrystallization events of two important cryoprotective solutions. DSC results showed the nanoparticles had little effect on the glass transition temperatures and melting temperatures of quenched solutions, but had significant effects on the devitrification and recrystallization during the heating process. Atrous et al.34 used DSC to study the effect of γ-radiation on the structural change of wheat starch. The DSC thermograms of native and irradiated wheat starches showed the absence of significant differences in the gelatinization temperatures, as well as the corresponding transition enthalpies since the DSC parameters are related to the crystalline ordering within the granules. de Oliveira et al.35 used DSC to evaluate thermal behaviours of palm oil and blends of palm and canola oils with additives (sorbitan monostearate or hydrogenated canola oil). The DSC results showed the additives increased thermal resistance of the samples. Le-Bail et al.36 used DSC to analyze thermal stability of amylose-unsaturated fatty acid complexes obtained by hydrothermal processing. DSC thermograms showed the melting/recrystallization of such complexes was almost reversible at the given heating/cooling rates. Shi et al.37 used DSC to study the effect of storage temperature on recrystallization and in vitro digestibility of wrinkled pea starch gel. DSC thermograph showed all the recrystallized starches had the decreasing temperature parameters and enthalpy compared with native pea starch. However, the temperature parameters and enthalpy of starch stored at cycles of 4 ℃ for 1 day and subsequently 30 ℃ for 1 day were higher than those of starches stored at 4 and 30 ℃。



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2.2.2. Differential thermal analysis DTA technique is similar to DSC technique except that it is to measure the temperature difference between the sample and the inert reference (generally α-Al2O3) as a function of temperature. DTA curves can provide data on the transformation including glass transitions, crystallization, melting, sublimation, and etc. Every kind of materials has their own differential thermal curves, and therefore DTA is an important way to analyze the physical properties of materials, especially crystals. DTA has been widely applied for studies of drug/food crystals. El-Gizawy et al.38 used DTA to study thermal behaviour of hydrochlorothiazide, aerosil and their complex formulations (Figure 5). DTA thermograms and the calculated thermodynamic parameters indicated the addition of aerosil into the complex formulations and suggested the addition of aerosil might induce the cocrystal formation in the prepared formulations. Qiu et al.39 prepared starch nanoparticles with controllable sizes and used DTA to analyze the degradation temperature. DTA curves showed the maximum degradation temperature decreased with the increase of the volume ratio of starch solution to absolute ethanol in the nanoprecipitation preparation process. The results demonstrated the compact semi-crystalline structure of native starch required more energy to complete degradation during TGA determination. All these works proved DTA is an useful tool to analyze the properties of drug/food crystals. 2.2.3. Thermogravimetric analysis TGA, also named as thermal gravimetric analysis, is a thermoanalytical technique to measure the mass amount as a function of temperature. It is suitable for checking the loss of solvent in the crystal or the sublimation and decomposition process of a sample. TGA curves can be applied to speculate whether the crystals contain water or solvent, and therefore it can be used to fastly distinguish water-free crystal structure and pseudo polymorphs. The method has several advantages such as simple operation, high sensitivity, reproducibility, and less 10 ACS Paragon Plus Environment

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sample amount. It is commonly used for the analysis of drug polymorph. But, it is generally combined with other instrumental analytical techniques such as XRD, IR, and Raman because it is difficult to determine drug polymorph. TGA has been widely applied for studies of drug/food crystals. Liu et al.40 synthesized hydroxy zinc phosphate particles for drug-loading of epirubicin and used TGA to analyze the hydroxy zinc phosphate particles (Figure 6). TGA curves showed the weight loss (at the temperature range of 0-200 ℃) corresponding to the loss of physically adsorbed water, weight loss (at the temperature range of 200-400 ℃) corresponding to the loss of lattice water, and weight loss (at the temperature range of 400-600 ℃) corresponding to the gradual dehydroxylation of the particles. The TGA results also showed thermal stability of the particles obtained at higher reaction temperatures was better than that of the particles obtained at lower reaction temperatures. These TGA results were consistent with XRD results. This work is a typical application example of TGA for the analysis of water content in crystals. Chen et al.41 synthesized polymer Eudragit RL100-coated drug Griseofulvin crystals and used TGA to analyze their thermal behaviors. According to the TGA results, the weight of the polymer coating was calculated to be 12% and the polymer coating thickness was estimated to be 75 nm. This work proved that TGA is an effective way to analyze the coating mass ratio and thickness on the drug crystals. Soni et al.42 prepared transparent bionanocomposite films based on chitosan and 2,2,6,6-tetramethylpiperidine-1-oxyl radical-oxidized cellulose nanofibers and used TGA and XRD to evaluate thermal properties and crystal structure of the films. XRD results indicated the films were mainly in crystalline form. TGA results showed these films had high thermal stability, which is mainly due to the presence of the crystalline structures. The work showed a typical example how TGA combined with XRD to study potential crystal materials. 2.3. Molecular vibrational spectroscopy



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Molecular vibrational spectroscopy is a branch of molecular spectroscopy and can be classified into infrared (IR) and Raman spectroscopy. Molecular transitions involve changes in both vibrational and rotational states. For different crystals, the bond lengths and bond angles are different, and therefore the vibrational and rotational energy levels are different. Hence, different crystals have different vibrational spectra. 2.3.1. Infrared spectroscopy For different crystals, the IR spectra showed different characteristics such as the frequency, peak shape, peak position, and peak intensity of the adsorption band.44-45 The common sample preparation methods for IR spectroscopy include KBr pellet pressing method, nujol mull method, film method, liquid membrane, liquid pool method, and etc. Currently, KBr pellet pressing method is the most applied method for the analysis of drug/food crystals. Taking into account the grinding may lead to the change of the drug crystal structures, nujol mull method is the most promising method. IR spectroscopy is a simple and fast way to differentiate varieties of crystals. However, it should be noted that it is difficult to differentiate those crystals who have the same IR spectra but different crystal structures. For example, IR spectroscopy cannot be applied to differentiate phenethyltropine hydrochloride form I and form II because they have the same infrared spectra.46 In addition, impurity and crystal transformation may also induce different spectra, which will make it is difficult to recognize these possible factors. At this kind of situation, it is necessary to analyze the crystal structure by combining with other methods. IR spectroscopy has been widely applied for studies of drug/food crystals. Guo et al.47 prepared rod-shaped and sphere-like lovastatin nanocrystals by snooprecipitation and bead milling. Then they used IR and other techniques to characterize the crystals and demonstrated the chemical structure of lovastatin did not alter during the preparation process. Wijayasinghe et al.48 used DSC and fourier transform (FT)-IR to establish the crystallization nature of freeze-dried lactose with or without lactic acid. FT-IR spectra showed the hydration layer 12 ACS Paragon Plus Environment

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consisting lactic acid and H3O+ ions surrounded lactose molecules via strong H bonds. The layer established unfavorable conditions for lactose crystallization. This work suggested partial or complete removal of lactic acid from acid whey might improve lactose crystallization ability and promote the processing development of acid whey. Xia et al.49 studied the structure and properties of starch modified with citric acid after hydrothermal pretreatment (Figure 7). FT-IR spectra indicated the esterification of starch modified with citric acid was weaker than that of starch modified with citric acid after hydrothermal pretreatment. Combined with other results, this work showed that hydrothermal pretreatment could increase the accessibility of the starch granules and make the starch easily used in food industry. 2.3.2. Raman spectroscopy Raman spectroscopy is an analytical method to observe vibrational, rotational, and other low-frequency modes of a substance based on Raman scattering.50 Some non-polar groups have no obvious absorption in IR spectra but have obvious spectroscopic characteristics in Raman spectra. No special treatment of sample preparation is necessary for the measurement of Raman spectroscopy, and therefore, the crystal structure of the sample may not be altered during the sample preparation process, which is beneficial to the crystal structure analysis of the sample. Raman spectroscopy has been widely applied for studies of drug/food crystals. Nyström et al.51 applied several techniques such as XRD and Raman spectroscopy to study the solid state transformations of piroxicam in consequence of electrospraying. Raman spectroscopy demonstrated the piroxicam after electrospraying was different to both the amorphous form and I-form of piroxicam (Figure 8). Combined with other crystallization techniques, this work indicated the electrospraying process leaded to a novel polymorphic form of piroxicam. Luo et al.52 synthesized amylose-zinc inclusion complexes and characterized them by several techniques including Raman spectroscopy. Raman spectra showed the amylose-zinc inclusion 13 ACS Paragon Plus Environment


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complexes and amylose had similar basic skeletons. The presence of zinc induced the formation of a special single helix structure of the amylose. Further, XRD results confirmed the complexes were mainly V crystal structure and minorly B crystal structure compared with that amylose was typical B crystal structure. Chen et al.53 developed a novel method for continuous polymer coating of drug crystals based on solid hollow fiber cooling crystallization. Raman spectra showed the polymer coating did not change the drug crystal structures, which was further confirmed by XRD. Therefore, this polymer coating technique had a promising future in the pharmaceutical industry. All these works demonstrated Raman spectroscopy was an useful tool for the research and development of drug/food crystals. In the past thirty years, with the development of computer and analytical software, Near infrared Fourier transform Raman spectroscopy has been applied to qualitatively and quantitatively study drug/food polymorphs.54-56 It has the advantages of near infrared such as no sample destruction, no necessity to use dissolution solvents, and capability of in situ measurements. Moreover, it also has the advantages of Raman spectroscopy such as no special sample preparation process and high sensitivity to the change of the solid polymorphs. However, it was not widely applied in drug/food crystal studies recently,57 which might be resulted from low performance/price ratio compared with other crystal characterization techniques. 2.4. Microscopy observation techniques Seeing is believing. Therefore, direct observation of the crystal by microscopy is a pivotal analytical way to study the crystals in pharmaceutics and foods. Until now, four types of microscopy techniques have been applied in this field: polarized light microscopy (PLM), hot stage microscopy (HSM), atomic force microscopy (AFM), transmission electron microscopy (TEM), and scanning tunneling microscopy (STM).


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2.4.1. Polarized light microscopy PLM, also named as optical polarization microscopy, means a type of optical microscopy technique that uses polarized light to illuminate the sample.58 In a polarized light microscope, a polarizer under sample stage is applied to convert the incident light into polarized light and an analyzer in lens cone is applied to receive the transmitted polarized light. PLM is most commonly used on transparent birefringent samples such as crystals where the polarized light strongly interacts with the sample and generate constrast with the background. The observation of transparent solid drug/food crystal is usually carried out under the crossed polarized light. When the sample is rotated on the sample stage, the optical image will show a transient disappearance (extinction) and appearance because of the different crystal structure and the birefringence effect of polarized incident light. The obtained extinction angle from the axis of the crystal that it must be rotated to appear the extinction state is related to the crystal forms. Further, PLM can be used to study the phase transition of crystal forms and accurately determine the melting point of crystals. PLM has been widely applied for studies of drug/food crystals, including animal/plant crystal materials (fibrins, starch granules, and etc.). Lim et al.59 developed an injectable liquid crystal system for sustained delivery of entecavir. PLM was applied to investigate the structure of the liquid crystalline phase and confirmed their typical characteristics and recognized them as the hexagonal phase. Duncke et al.60 used PLM to study lamellar liquid crystals in emulsion fractions from Brazilian crude oils. Several structures exhibiting Maltese cross-optical pattern and mostly in aqueous-rich fractions (bottom fractions). Shrestha et al.61 used PLM to observe the hygroscopic swelling behaviors of self-organized and shear-oriented cellulose nanocrystal films. Shear-oriented films had a highly anisotropic hygroscopic expansion than self-organized films did. Nie et al.62 used PLM to analyze the effects of crystalline solid despersion (ASD) in solid formulations on the salt disproportionation (a conversion from the ionized to the neutral state). The PLM results showed hypromellose 15 ACS Paragon Plus Environment


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acetate succinate had a better inhibitory effect on the crystallization of pioglitazone free base compared with vinylpyrrolidone-vinyl acetate (Figure 9). These results demonstrated the salt disproportionation can be slowed down during storage and wet granulation by adding a crystalline salt into a polymeric carrier. These works proved PLM is an effective way to directly observe crystals and to analyze their behaviors and affecting parameters. 2.4.2. Hot stage microscopy HSM is a combination of microscopy and thermal analysis to enable the direct observation of materials by microscopy as a function of temperature and time. HSM is generally performed by a polarized optical microscope equipped with a heat/cool stage. HSM can directly observe thermal dynamic process (phase transition, melting, decomposition, recrystallization, and etc.) of crystals. HSM has been widely applied for studies of drug/food crystals. Hean et al.63 synthesizd an isoniaide derivative and studied the crystal structure by HSM and other techniques. HSM was used to in situ analyze the melting point and thermal phase transition (Figure 10). The HSM results showed irreversible phase transitions at about 129 ℃. Further, HSM directly observed six types of crystal forms during the recrystallization on slow cooling or on reheating process. Vangala et al.64 used HSM to in situ study thermodynamic behaviors of a dimorphic (Forms I and II) co-crystal system (1:1 caffeine−glutaric acid). HSM results agreed well with the DSC results. HSM visualized the melting of Form II at about 98 ℃. Especially, HSM visualized the nucleation and growth of needle-shaped Form I on the surface of Form II crystal. Noonan et al.65 used HSM to observe the polymorphism of the antiviral agent clevudine at different temperatures. HSM observed the crystals of the various forms (Form I, II, and III) at different temperatures and demonstrated their obvious difference. Jaywant et al.66 prepared efavirenz cocrystals from stoichiometric solutions by spray drying technology and analyzed by HSM and other techniques. HSM results showed the visual thermal transitions and the extent of drug melting within glutaric acid. It confirmed the homogeneity 16 ACS Paragon Plus Environment

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of the cocrystal system and proved the spray drying technology had a big potential in the pharmaceutical industry. Carvalho et al.43 synthesized the racemic polymorphs of fluoxetine nitrate and then used DSC, TGA, and HSM to study thermal properties of polymorphs. Though HSM and DSC/TGA were performed under different atmospheres, it is worth noting that all the results were in good agreement to each other. It built a good example to apply TGA, DSC, and HSM to study the same materials. All these works proved HSM can contribute significantly to help study thermal changes of drug/food crystals and is a powerful and versatile technique in the field of crystal analysis. 2.4.3. Atomic force microscopy AFM uses a sharp tip to image the sample surface, measure the nanomechanical properties of the sample surface, and manipulate the sample surface at nanoscale level.67-70 In the past three decades, it has been widely applied in the physical, chemical, materials, biological, and medical sciences. The samples can be imaged in high vacuum, under atmosphere, or in liquid. Compared with other nanotechniques, it has many advantages such as high resolution, capability of imaging of 3D structure of the samples, capability of in situ observation, and capability of nanomechanical analysis and nanomanipulation. AFM has been widely applied for studies of drug/food crystals. Reischl et al.71 studies the surface-induced polymorphism to enhance dissolution of model drug phenytoin. AFM was applied to directly observe the nanomorphology of the phenytoin onto silicon dioxide surfaces. The large single-crystalline domains of the surface-induced polymorph was observed. AFM results gave direct and visible characteristics for the crystal analysis. Olafson et al.72 used AFM to time-lapse in situ image the crystallization process of hematin crystal (Figure 11) and the growth inhibition of hematin crystal by chloroquine (a common quinoline antimalarial drug). The crystallization strictly followed a classical 2D nucleation and growth mechanism. The crystal growth inhibition by chloroquine was resulted from their adsorption at specific growth sites on the hematin crystals. The AFM results provided the first evidence of the 17 ACS Paragon Plus Environment


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molecular mechanisms of crystallization and inhibition. Rime et al.73 used AFM to analyze the effect of crystal growth inhibitors (L-cystene dimethylester and L-crystal methylester) on the crystallization of L-crystine, which is pivotal in the pathogenesis of cystine kidney stones. The results showed these inhibitors dramatically reduced the growth velocity of L-crystine crystals by their specific binding at the crystal surface. These works proved AFM is an effective way to analyze the morphologies of crystals and study the interaction mechanisms between crystals and other substances. 2.4.4. Transmission electron microscopy TEM is a microscopy technique using an electron beam to transmit through a specimen to form an image. It is similar to light microscopies but has a significantly higher resolution than light microscopies because of the application of electron beam. The samples are imaged in high vacuum and are most often ultrathin sectiones of less than 100 nm thick or a dried suspension on a grid. It can be applied to analyze crystal morphologies, crystal structure, crystal orientation, crystal lattice defects, and etc.74 TEM has been widely applied for studies of drug/food crystals. Sun et al.75 prepared waxy maize starch nanoparticles through enzymolysis and recrystallization and used TEM to observe the morphologies of these nanoparticles. The results showed these nanoparticles were well dispersed without aggregation and had sizes of 50-100 nm width and 80-120 nm length. The TEM results proved the developed preparation method was a promising method to prepare starch particles with good shapes. Wang et al.76 used TEM to characterize novel mesoporous silica as oral solid dispersion carriers for water insoluble cilostazol. TEM results showed clear cubic pores or cylindrical mesopores with a size of about 4 nm. This work proved TEM is an effective tool to image crystals with special nanostructures. Ricarte et al.77 used TEM to study the crystallinity of griseofulvin/hydroxypropyl methylcellulose acetate succinate solid dispersions (Figure 12). TEM results showed both real-space images and electron diffraction patterns and identified griseofulvin crystals in spray dried solid 18 ACS Paragon Plus Environment

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dispersions. This work proved TEM is a promising technique for the characterization of even small degrees of crystallinity in solid dispersions. 2.4.5. Scanning electron microscopy SEM is a microscopy technique using an electron beam to image the surface of a sample.78-79 The electrons interact with the atoms on the surface and generate various signals that contain information about the samples surface topography and composition. The samples are imaged in high vacuum in conventional SEM or in low vacuum or wet conditions in variable pressure or environmental SEM. Especially, energy-dispersive X-ray spectroscopy can be applied as an accessary to SEM and can be used for composition analysis. SEM can be applied to analyze both crystals and noncrystals at nanoscale or microscale.80-81 SEM has been widely applied for studies of drug/food crystals. Waknis et al.82 used SEM to image crystal morphologies of mefenamic acid after recrystallization and observed the plate- and needle-shaped morphologies at different crystallization conditions. Dital et al.83 studied different effects of particle size, morphology, thermal properties and crystalline polymorph on rice starch granule amylolysis and used SEM to observe the granule sizes, shapes, and surface pores. Garcia et al.84 studied structures of glycerol monoestearate-maize starches complexes with different amylose contents and used SEM, AFM, and TEM to observe their morphologies (Figure 13). The images from SEM, AFM, and TEM can help the scientists to comprehensively understand the structure of normal maize-glycerol monostearate complexes. Zeng et al.85 studied the effect of different drying methods on the structure and digestibility of short chain amylose crystals and used SEM to observe their morphologies. The SEM showed clear morphologies of the amylose cystrals. All these works demonstrated that SEM is effective for crystal studies and could provide direct evidence for the analysis of drug/food crystals. 2.5. Solid-state nuclear magnetic resonance spectroscopy



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Solid-state nuclear magnetic resonance (SSNMR) spectroscopy is a powerful technique to analyze the structure and dynamics of many solid inorganic, organic and organometallic compounds and materials including crystals. There are slight differences in the chemical environment of the atoms in different crystal structures, resulting in different chemical shifts. They can be recorded by solid-state 13C-NMR spectra. The spectra can be applied to analyze the dynamics and chemical environments of the atoms in the crystals. Therefore, solid-state 13

C-NMR spectroscopy can be applied for crystal form analysis of mixed crystals and

determination of crystal forms. SSNMR spectroscopy has been widely applied for studies of drug/food crystals. Yang et al.86 developed a novel solution impregnation method to form organic nanocrystals polymer matrices and used magic angle spinning SSNMR spectroscopy to analyze the crystal forms of the drugs and the matrices. The SSNMR spectra demonstrated nanocrystal drugs were formed in the polymer matrices (Figure 14). It proved this novel solution impregnation method could be applied to prepare nanocrystals of poorly soluble drugs to improve their solubilities. Chattah et al.87 used magic angle spinning SSNMR spectroscopy to study albendazole Forms I and II, which showed obvious differences in both the peak positions and peak splitting. Pinon et al.88 used dynamic nuclear polarization enhanced SSNMR spectroscopy to study polymorphs and solvates of organic solids. The technique was applied to analyze three polymorphs and one hydrated form of the asthma drug theophylline. The effects of sample preparation parameters on the SSNMR results were studied and some suggestions for sample preparation were provided. All these works demonstrated SSNMR spectroscopy can provide useful crystal form information for the study of drug/food crystals. 2.6. Nuclear quadrupole resonance spectroscopy Nuclear quadrupole resonance (NQR) spectroscopy is a NMR-related chemical analytical technique. Unlike NMR, NQR transitions of nuclei can be detected in the absence of a magnetic field, and therefore, this technique is also named as “zero field NMR”. It can 20 ACS Paragon Plus Environment

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only be applied for solid materials because the chemical shifts were averaged to zero in liquid. The NQR frequency of a compound or crystal is proportional to the nuclear quadrupole moment, the nucleus, and the electric field gradient in the neighborhood of the nucleus. Therefore, this technique is very sensitive to analyze the local structure of materials, electronic density distribution near the nuclei under study, the nature of defects in solids.89 NQR spectroscopy can examine uniquely crystals containing quadrupolar nuclei whose spin quantum number is greater than 1, such as 14N and 35Cl.90 NQR spectroscopy has been widely applied for studies of drug/food crystals. Lavric et al.91 used

14

N NQR spectroscopy to study the polymorphic crystal forms of piroxicam. The

results showed a new crystal form, named as form V. This work proved NQR spectroscopy had a strong potential to be a highly discriminative spectroscopic analytical tool to detect polymorphic forms. Kyriakidou et al.92 used

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N NQR spectroscopy to detect the crystal

structures of different batches of analgesic paracetamol tablets. Statistical analysis of these NQR results showed a significant discrimination, even that 99.9% confidence interval, between the different batches. This work proved NQR spectroscopy can be applied to compare the crystal form discrimination of a large number of crystals by combining statistical analysis. Gregorovic et al.93 used

14

N NQR spectroscopy to quantitatively detect the phase

transformation of the anhydrous aminotetrazole to its hydrate, aminotetrazole monohydrate in real time. The results showed a linear relationship between NQR peak areas and the hydrate/anhydrate masses (Figure 15). This work proved NQR spectroscopy could be applied to monitor the hydration of crystals in real time. All these works showed NQR spectroscopy is effective for crystal studies. 3. Summary and outlook Up to now, many instrumental analytical techniques have been widely used for the characterization of crystals in pharmaceutics and foods. Without these techniques, no such huge advances have been made in the field of pharmaceutics and foods. Furthermore, these 21 ACS Paragon Plus Environment


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techniques can be applied as sensor technologies of process analytical technology for crystallization processes, which involves continuous monitoring and control of industrial crystallization process.7 Most of the methods mentioned above can only reflect a part of physicochemical properties of different crystals. Therefore, the combination of different analytical techniques can provide a comprehensive understanding of the drug/food crystals.9495

The application of these instrumental analytical techniques are pivotal for new drug/food

development, formulation design of drug/food, optimization of production process, quality control, optimization of storage condition, understanding of bioavailability and efficacy, and etc. We believe that more and more techniques will be developed for drug/food crystal studies with the advance of science and technology.

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Figures Figure 1

Figure 1. Common instrumental analytical techniques for the characterization of crystal structures in


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pharmaceutics and foods



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Figure 2

Figure 2. PXRD patterns of quercetin dehydrate (Quer_dihy) and two commercial quercetin dietary supplements (Quer_O: a type of tablet; Quer_N: a type of capsule). The excipients were indicated by arrows: orange-magnesium stearate/stearic acid, red-ascorbic acid, brown-silica. Reprinted with permission from ref. 16. (Copyright 2016 Elsevier Inc.).


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Figure 3

Figure 3. The determined crystal structures of (a) melatonin, (b) pimelic acid, and (c) melatonin-pimelic acid cocrystal by using SCXRD. Reprinted with permission from ref. 19. (Copyright 2015 Royal Society of Chemistry).



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Figure 4

Figure 4. DSC curves of native starch and esterified starch. Reprinted with permission from ref. (Copyright 2013 Elsevier Inc.).


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Figure 5

Figure 5. DTA thermograms of (a) aerosil, (b) pure unprocessed drug hydrochlorothiazide, (c) wet ground drug hydrochlorothiazide, (d) hydrochlorothiazide/aerosil (1:1), (e) hydrochlorothiazide/aerosil (1:2), and (f) hydrochlorothiazide/aerosil (1:4). Reprinted with permission from ref. 38. (Copyright 2015 Elsevier Inc.).



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Figure 6

Figure 6. TGA curves of hydroxy zinc phosphate particles those were synthesized at different temperatures. Reprinted with permission from ref. 40. (Copyright 2015 Royal Society of Chemistry).


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Figure 7

Figure 7. FT-IR spectra of starch samples. (A): native starch, (B) citric acid-modified starch, and (C) citric acid-modified starch after hydrothermal pretreatment. Reprinted with permission from ref. 2016 Elsevier Inc.).


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. (Copyright


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Figure 8

Figure 8. Raman spectra of the original and electrosprayed piroxicam. Different regions were highlighted. Possible functional groups were labeled. Reprinted with permission from ref. 51. (Copyright 2015 Elsevier Inc.).


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Figure 9.

Figure 9. PLM images of amorphous solid dispersion (ASD) in solid formulations. (A): ASD of pioglitazone free base and hypromellose acetate succinate, (B) ASD of pioglitazone free base and vinylpyrrolidone-vinyl acetate, (C) ASD of pioglitazone free base and hypromellose acetate succinate stressed at 40℃/75%RH for 24 h, (D) ASD of pioglitazone free base and vinylpyrrolidone-vinyl acetate stressed at 40℃/75%RH for 24 h. The scale bars were 100 µm. Reprinted with permission from ref. (Copyright 2015 Elsevier Inc.).


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Figure 10

Figure 10. Polarized light HSM photomicrographs of a plate-like crystal of an isoniaide derivative during the temperature change. a) the crystal form V before transition at about 129 ℃, b) the transition with the proceeding transition interface. The position that was indicated by yellow arrows in b) showed the in situ observation of the phase transition until the crystal has completely transformed into crystal form III in c) and d). Reprinted with permission from ref. 63. (Copyright 2015 Royal Society of Chemistry).


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Figure 11.

Figure 11. Generation of hematin crystal layers. (A-D) In situ AFM observation of the crystallization process of hematin crystal on a (100) face at a concentration of 0.25 mM. Arrows indicate newly nucleated islands (I-V). Islands (I-III) grow with time. Island IV dissolves with time. Island V retains its size with time. Scale bar is 125 nm. (E) The critical radius of 2D nuclei as a function of In(CH/Ce). CH is hematin concentration. Ce is hematin solubility in the solvent. The solid line is the predicted trend based on the Gibbs-Thomson relation with surface free energy 23 mJ/m2 estimated using the Turnbull empirical rule. (F) Rate of 2D nucleation of new layers as a function of In(CH/Ce). The solid line is interpolated to guide the eye. Reprinted from ref. 72. (Copyright 2015 National Academy of Sciences).



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Figure 12.

Figure 12. TE micrographs of 50 wt% griseofulvin solid dispersion that was annealed on a TEM grid at 130 ℃ for 12 h. (a) Bright-field TEM. (b) A higher magnification of the circled region in (a). (c) Electron diffraction pattern. (d) Dark-field TEM. (c) and (d) confirmed the region is crystalline. Reprinted with permission from ref. 77. (Copyright 2015 American Chemical Society).


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Figure 13.

Figure 13. SEM (A-C), 3D AFM (D, E), and TEM (G) images of normal maize (NMS)-glycerol monostearate (GMS) complexes. NMS-1%GMS complex: (A, D, and G). NMS-2%GMS complex: (B). NMS-3%GMS complex: (C and E). Reprinted with permission from ref. 84. (Copyright 2016 Elsevier Inc.).



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Figure 14.

Figure 14. SSNMR spectra of form I ibuprofen (top) and cellulose-ibuprofen (bottom). The cellulose resonance is located the positions >50 and

Instrumental Analytical Techniques for the Characterization of Crystals

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