Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometry

ADR-12899; No of Pages 11 Advanced Drug Delivery Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr

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Seema Thakral a,b, Maxwell W. Terban c, Naveen K. Thakral a,d, Raj Suryanarayanan a,⁎

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Article history: Received 22 October 2015 Received in revised form 10 December 2015 Accepted 12 December 2015 Available online xxxx

Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States Characterization Facility, University of Minnesota, Minneapolis, MN 55455, United States Department of Applied Physics and Applied Mathematics, Columbia University, New York, NY 10027, United States d Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States b

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For poorly water soluble drugs, the amorphous state provides an avenue to enhance oral bioavailability. The preparation method, in addition to sample history, can dictate the nature and the stability of the amorphous phase. Conventionally, X-ray powder diffractometry is of limited utility for characterization, but structural insights into amorphous and nanocrystalline materials have been enabled by coupling X-ray total scattering with the pair distribution function. This has shown great promise for fingerprinting, quantification, and even modeling of amorphous pharmaceutical systems. A consequence of the physical instability of amorphous phases is their crystallization propensity, and recent instrumental advances have substantially enhanced our ability to detect and quantify crystallization in a variety of complex matrices. The International Centre for Diffraction Data has a collection of the X-ray diffraction patterns of amorphous drugs and excipients and, based on the available supporting information, provides a quality mark of the data. © 2015 Published by Elsevier B.V.

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Keywords: Amorphous Crystallization Total scattering pair distribution function Solid dispersion X-ray diffractometry

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1. Introduction . . . . . . . . . . . . . . . . . . . . . . 2. Standards and databases . . . . . . . . . . . . . . . . 3. Amorphous phases — conventional characterization by XRD 4. Total scattering pair distribution function (PDF) . . . . . . 5. Processing-induced phase transformation . . . . . . . . . 6. Quantification using XRD . . . . . . . . . . . . . . . . 7. Future technology . . . . . . . . . . . . . . . . . . . 8. Summary . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .

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Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometry☆

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Abbreviations: API, active pharmaceutical ingredient; ASD, amorphous solid dispersion; HPMC, hydroxypropylmethyl cellulose; HPMCAS, hydroxypropylmethyl cellulose acetate succinate; ICDD, International Centre for Diffraction Data; MC, methyl cellulose; NIST, National Institute of Standards and Technology; PC, principal component; PDF, total scattering pair distribution function/Pair distribution function; PEG, polyethylene glycol; PLS, partial least square; PVP, polyvinyl pyrrolidone; TEM, transmission electron microscopy; USP, United States Pharmacopeia; XRD, X-ray diffraction or X-ray diffractometry. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Amorphous pharmaceutical solids”. ⁎ Corresponding author. E-mail address: [email protected] (R. Suryanarayanan).

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1. Introduction

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Amorphous (also referred to as non-crystalline) pharmaceuticals are characterized by the absence of long-range lattice periodicity of the constituent molecules. A number of active pharmaceutical ingredients (API) including cefuroxime axetil (Ceftin®), quinapril hydrochloride (Accupril®) and zafirlukast (Accolate®) exist in the amorphous state in marketed drug products [1]. Several excipients including ethyl cellulose, hydroxylpropyl cellulose, and hydroxypropylmethyl cellulose (HPMC) are inherently amorphous. The transition of a drug substance into a solid dosage form entails numerous processing steps. Unintended

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Please cite this article as: S. Thakral, et al., Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometry, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.12.013

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and erythromycin ethyl succinate. In the individual monograph of these drugs, typically, there is a recommendation for the method of determination of the amorphous content. The monographs of suspension formulations of insulin specifically define the amorphous content in the formulations. Both Insulin Zinc Suspension and Insulin Human Zinc Suspension consist of a mixture of crystalline and amorphous insulin in a ratio of approximately 7 parts of crystals to 3 parts of amorphous material. In the case of Prompt Insulin Zinc Suspension, the solid phase of the suspension is amorphous. The United States Pharmacopoeia has a number of “General Chapters” dealing with identification and quantification of the amorphous content, both in drug substances and drug products [18]. In addition to XRD, calorimetric, microscopic, and spectroscopic techniques can be used for this purpose. For qualitative purposes (amorphous or crystalline), the technique of choice in USP is polarized light microscopy. The absence of birefringence is considered a characteristic feature of amorphous phases. The National Institute of Standards and Technology (NIST) has developed Standard Reference Materials for X-ray diffraction metrology with respect to: i) line position, ii) line profile, iii) instrument response, iv) quantitative analysis, and v) thin film characterization. While X-ray diffraction finds extensive use for simultaneous quantification of multiple crystalline phases, quantification of the unknown amorphous fraction has been enabled with the certification of NIST Standard Reference Materials for absolute phase purity [19]. The International Centre for Diffraction Data (ICDD) is dedicated to collecting, editing, publishing and distributing powder diffraction data for the identification of materials. The powder diffraction file database developed by ICDD provides “fingerprint” of crystalline compounds based on the d-spacing (determined from the angle of diffraction) and the intensity of the diffracted radiation. The PDF-4/Organics 2016 database has 10,780 entries of pharmaceuticals (including 2667 entries for excipients) [20]. Out of these, 23 entries are for amorphous APIs and 10 entries are for amorphous excipients (Table 2). Fig. 1 is an overlay of the XRD patterns of representative amorphous drugs and excipients from this database. The amorphous excipients are predominantly celluloses, dextrans, and povidones. Based on the available supporting data, ICDD has given a quality mark of “G” (good) or “M” (marginal) for the amorphous patterns in the database.

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3. Amorphous phases — conventional characterization by XRD

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In general, comprehensive characterization of amorphous phases necessitates the use of multiple analytical techniques. In addition to XRD, thermoanalytical techniques and spectroscopy are extensively used by the pharmaceutical community [21]. This review will focus exclusively on the use of X-ray diffractometry. Historically, in the

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According to the United States Pharmacopeia (USP), the amorphous state is one in which, “….a solid contains the maximum possible density of imperfections (defects of various dimensionalities), such that all long-range order is lost while only the short-range order imposed by its nearest neighbors remains” [18]. In the USP, there are a number of monographs on amorphous drugs including azithromycin, cefuroxime axetil, losartan potassium, warfarin sodium, doxorubicin hydrochloride

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Table 1 Representative list of marketed solid dispersion formulations. A large fraction of these dispersions were introduced within the last ten years reflecting the increase in the number of poorly water soluble drug molecules in the discovery/development pipeline (adapted from references [11,12]).

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amorphization of pharmaceuticals may be induced during pharmaceutical processing steps such as milling and compression [2]. Processinginduced phase transformations are discussed in detail in a later section. A large fraction of new drug candidates in the pipeline suffer from the problem of low aqueous solubility [3]. Drug amorphization is a very promising approach to enhance the apparent solubility and consequently the oral bioavailability of these new drug candidates [4]. The amorphous form can have an apparent solubility value orders of magnitude higher than that of its crystalline counterpart [5,6]. On the other hand, owing to its higher free energy, its potential physical instability leading to crystallization is a major practical challenge. Amorphous solid dispersion (ASD), a homogeneous drug–polymer mixture, is a popular and well-tested approach to physically stabilize amorphous drugs [7,8]. ASDs also provide an avenue for enhancing the oral bioavailability. For example, α-pentyl-3-(2-quinolinylmethoxy) benzenemethanol (aqueous solubility ~ 2 μg/mL at pH 6; 37 °C) was formulated as an ASD and its oral bioavailability was compared with that of a conventional tablet formulation containing crystalline active ingredient. The plasma area under the curve ratio of the ASD to tablet was found to be 3.3 [9]. In cynomolgus monkeys, an ASD of a vanilloid receptor antagonist (AMG 517; aqueous solubility b0.3 μg/mL in phosphate buffer saline at pH 7.1) exhibited 163% area under curve when compared to an oral suspension [10]. The popularity of the technique is evident from the number of dispersion formulations in the market (Table 1). The amorphous state is also of interest when dealing with freezedried pharmaceuticals. Rapid reconstitution of a freeze-dried product is enabled by retaining all the formulation components, including the drug, in the amorphous state. For example, partial crystallization of indomethacin sodium in a freeze-dried product resulted in an increase in reconstitution time from 11 to 57 s [13]. Thermolabile pharmaceuticals, specifically proteins, are often marketed in the freeze-dried state. Their stability can be enhanced by the addition of a lyoprotectant to the formulation [14,15]. In order to be effective, the lyoprotectant must be retained in the amorphous state. Lyoprotectant crystallization might potentially impact the stability of proteins [16]. XRD is widely used to characterize the final formulation and to ensure the amorphous state of the lyoprotectant. [17].

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Incivek Kalydeco Zelboraf Norvir Zortress Intelence Fenoglide Kaletra Crestor Rezulin Prograf Sporanox Nimotop Cesamet Gris-PEG

Telepravir Ivacaftor Vemurafenib Ritonavir Everolimus Etravirine Fenofibrate Lopinavir/Ritonavir Rosuvastatin Calcium Troglitazone Tacrolimus Itraconazole Nimodipine Nabilone Griseofulvin

Hepatitis C Cystic fibrosis Melanoma HIV Immunosuppressant HIV Hyperlipidemia HIV Lipid lowering agent Diabetes Immunosuppressant Anti-fungal Calcium channel blocker Antiemetic Antimycotic

HPMCAS HPMCAS HPMCAS Copovidone HPMC HPMC PEG 6000, Poloxamer 188 Copovidone HPMC PVP HPMC HPMC PEG PVP PEG 400, PEG 8000

Vertex Vertex Roche Abbott Novartis Tibotec/J&J Santarus Abbott AstraZeneca Wyeth Fujisawa Janseen/Ortho McNeil Bayer Valeant Pharma Pedinol Pharma

2011 2011 2011 2010 2009 2008 2007 2005 2003 1997 1994 1992 1988 1985 1975

Please cite this article as: S. Thakral, et al., Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometry, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.12.013

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Table 2 List of amorphous excipients in PDF-4/Organics 2016 [20]. PDF #

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(C8.45H14.9O5)n (C4H8O2)n. (C2H4O2)n C164H174O111 C116H116O64

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G G G G G G

H(C6H10O5)n OH (C6H10O5)n (C6H9NO)n (C6H9NO)n (C4H6O2)n (C6H9NO)n

Methyl cellulose, amorphous Cellulose acetate butyrate Cellulose acetate Cellulose acetate phthalate, amorphous Dextran-4, amorphous Dextran-250, amorphous Povidone, amorphous Copovidone, amorphous Polyvinyl pyrrolidone (PVP) Pepsin A

The two maxima in the diffractograms of the ball milled γ- and αforms and the cryomilled α-form occurred at approximately the same angles and were of similar intensities. The preparation method was reported to yield reproducible results. There were discernible differences in the diffraction pattern of amorphous trehalose prepared by freeze drying, spray drying and dehydration of trehalose dihydrate (Fig. 2b [30]). These differences were attributed to preparation-method induced structural variations in the near order of the molecules. Amorphous materials prepared by different methods also demonstrated pronounced differences in their crystallization behavior. Surana et al. compared the crystallization kinetics of amorphous trehalose prepared by freezedrying, spray drying, melt quenching and dehydration of trehalose dihydrate [31]. The amorphous trehalose prepared by dehydration crystallized rapidly, an effect attributed to existence of nuclei in the material. In a subsequent study, the preparation method was found to significantly affect the molecular mobility, measured as the structural relaxation time. There was an excellent correlation between crystallization time and relaxation time suggesting a similar molecular origin for these two processes [32]. Small changes in the water content of amorphous polymers can be evident from subtle differences in their XRD patterns. Depending on the water vapor pressure to which it is exposed, methyl cellulose (MC) retains 2–5% w/w water at room temperature. The XRD patterns of MC with about 3% water and the vacuum dried material are overlaid in Fig. 3. Vacuum drying removes the water almost completely and the consequent realignment of polymer chains is revealed in the XRD patterns [20]. Similarly, the peak positions and shapes of the amorphous halos in the XRD patterns of PVP (K-12 and K-90) varied as a function of the water content [33]. Upon increasing the water content, there was a gradual and progressive shift in the peak positions which was attributed to a change in PVP structure at molecular scale. Interestingly, at high water content (~45% w/w), the high angle halo displayed a shoulder resembling the halo for pure water. Chemometric analysis suggested clustering of water in PVP–water mixtures, where water at the boundaries of these clusters is most likely bonded to the polymer (Fig. 4).

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4. Total scattering pair distribution function (PDF)

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As mentioned earlier, the XRD pattern of an amorphous compound is characterized by one or more broad “halos”. Such a pattern, in itself, does not directly provide insight into the structure of the amorphous system [34]. An amorphous compound (this can be thought of as a super-cooled liquid) can be considered as an arrangement of locally ordered domains, with only short range order (SRO), isolated from each other by high energy barrier microstructure. The loss of long range order (LRO) symmetry operators (translational, orientational and conformational), leads to amorphization (disordering of the crystalline phase) [35]. The relationship between crystalline and amorphous states in terms of ‘thermodynamic’ and ‘kinetic’ disordering process has been

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characterization of amorphous phases, XRD served the role of confirming the absence of crystalline phases. However, in recent years, XRD has been used for the direct characterization of amorphous phases [22]. For most investigations of pharmaceutical interest, powdered samples are used. However, with recent instrumental advances, it is possible to analyze systems during the various stages of pharmaceutical processing. For example, the entire freeze-drying cycle can be simulated in a powder X-ray diffractometer [23,24]. It is also possible to directly analyze the final dosage form including intact tablets [25–27]. Instrumental advances, some of them recent, have substantially enhanced the utility of the X-ray diffractometric technique. An X-ray diffractometer with an area detector provides a two-dimensional image and is therefore referred to as two-dimensional diffraction. The data collection time with this setup is usually several orders of magnitude shorter than with conventional point detectors. Since a substantial part of the diffraction ring is collected, errors due to preferred orientation can be significantly reduced [28]. The rapid data collection, the enhanced signal intensity (two-dimensional image), and the potential reduction in errors due to preferred orientation make twodimensional diffraction particularly well suited for quantitative analyses of complex systems containing multiple analytes. The use of synchrotron radiation offers additional advantages including high brilliance, low divergence, and wavelength tunability thereby enhancing the sensitivity and resolution. When a compound is amorphized by different methods, the resulting XRD patterns may not be superimposable. Karmwar et al. [29] prepared amorphous indomethacin by ball-milling, cryo-milling, or quench-cooling crystalline (γ-form) indomethacin and also spraydrying a methanolic solution of the compound. Amorphous indomethacin was also prepared by ball milling and cryo-milling the α-form (Fig. 2a). Only the spray-dried sample was characterized by a single broad halo. Quench cooling or cryomilling of the γ-form yielded a halo with two maxima — the first at ~ 21° 2θ and the second at ~ 15° 2θ.

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Fig. 1. Overlay of XRD patterns of representative amorphous (a) drugs and (b) excipients from the library of amorphous substances in PDF-4/organics 2016 database. Data provided by ICDD [20].

Please cite this article as: S. Thakral, et al., Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometry, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.12.013

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or G(r) is obtained through an inverse Fourier transform of the reduced total scattering structure function F(Q), which is the background subtracted, corrected, and normalized diffracted intensity including both Bragg and diffuse scattering. In the case of X-ray amorphous materials, it may be only diffuse scattering in the measurement. It is this diffuse scattering, often ambiguous to interpret in reciprocal space, which becomes more straightforward when viewed in the context of the PDF. In practice, this can be measured in the same fashion as a standard powder X-ray experiment, except that scattering intensity should be collected to as high a scattering momentum transfer as possible, Qmax, where the magnitude Q = 4π sin θ/λ with scattering angle 2θ and wavelength λ. More in-depth resources are available on the theory and general application of this technique [22,38]. Here, our focus is on its use in the analysis of disordered pharmaceutical materials. Optimal measurement is achieved using high energy radiation to access a wide Q-range and high flux for improved data statistics. Synchrotron (or neutron) light sources are therefore ideal for PDF experiments, although neutrons may not be optimal for organic materials due to the high hydrogen content. For practical reasons, a user may wish to use inhouse X-ray sources. Sufficient and satisfactory data can be collected using Ag or Mo anode sources, though this may necessitate long acquisition times [39,40]. A rapid acquisition measuring mode can be used in both cases to improve data quality and to reduce collection times. Cu anode sources on the other hand do not provide a high enough Qmax for reliable PDF measurement [39]. The use of a two-dimensional area detector dramatically increases the number of captured photons, and by placing the detector close to the sample, the accessible Qmax can be increased [41]. Another option for in-house measurements is to use a transmission electron microscope (TEM). Sample preparation and measurement has been demonstrated using a standard laboratory TEM [42]. Further work demonstrates the use of TEM and scanning transmission electron microscope modes for measuring organic materials and methods for avoiding beam damage [43]. PDF can be used for exploring the effects of processing or storage on amorphous materials and may be employed as a tool for comparing different processing methods and to discern small structural differences. It is highly distinguishing between crystalline, nanocrystalline, and amorphous materials by observing the distances to which coherent structural correlations exist. For example, when indomethacin was rendered amorphous by melt quenching, the PDF exhibited loss of long range order (Fig. 6; [44]), whereas the crystalline parent compound is well ordered, exhibited by the presence of peaks at long distances. At the same time, the signal at short distances (i.e. the first few peaks) is approximately the same since both samples are chemically identical. Extraction of information about intermolecular packing, as in the case of glassy carbamazepine, cinnazirine, miconazole, clotrimazole, and probucol prepared by acoustic levitation [45], can be valuable for understanding product behavior.

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elegantly explained by Bates et al. (Fig. 5). Thermodynamic disordering results in random close packing, while in kinetic disordering, LRO is progressively reduced to MRO (Medium Range Order), and then to SRO [35]. Throughout this process, the spatial coherence of the structure diminishes. Starting with a well-ordered bulk crystal, gradual disordering processes will generate defects which continuously diminish the size of ordered domains until they reach some lower limit governed by the interactions between molecules within the local vicinity of one another. Analysis of the total scattering pair distribution function (PDF) or G(r) is a useful technique for extracting quantitative structural information from the sample, even when no long range order exists. It is a probe of the structure of the material, on the order of 1 to 100's of Å, giving a direct measure of the local structure of the components and the packing between them [36]. This can be used to study the structure of both crystalline and amorphous materials. The PDF gives the probability of finding two atoms separated by some distance r. Interatomic distances are given by the position of each peak with a magnitude representing the likelihood of finding atoms separated by that distance. This can be further understood as the probability of finding an atom-pair relative to the average atom-pair density of the material. Thus G(r) = 0 represents the average probability of finding an atom-pair. For example, in a well ordered material a well-defined atom-pair distance will give a strong positive peak while a distance where no atom-pair is defined may give a negative peak. For molecular materials, sharp intramolecular peaks at short distances are characteristic of the strong covalent bonding within a molecular species. For organic materials, the first few peaks generally represent carbon-carbon nearest-neighbor or nextnearest-neighbor bonds. The broader intermolecular peaks at longer distances represent the orientation and packing between molecules governed by hydrogen bonding or van der Waals forces [37]. The PDF

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Fig. 2. XRD patterns of amorphous APIs prepared by different methods. a) Amorphous indomethacin, QC (quenched-cooled; γ-polymorph), SD (spray dried; γ-polymorph), CM (cryomilled; γ, and α-polymorphs), BM (ball milled; γ, and α-polymorphs). b) Trehalose rendered amorphous by dehydration, lyophilization, and spray drying [30]. Panel a reproduced from reference [29], with permission of Elsevier.

Fig. 3. XRD patterns of methyl cellulose with 3% w/w water content (black) and vacuum dried (red; water content b0.5% w/w). Adapted from reference [20].

Please cite this article as: S. Thakral, et al., Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometry, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.12.013

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miscible systems, molecular level mixing should yield a third “constituent” — a consequence of API-excipient interactions. This should lead to poor fitting from the reference data or scale factors which deviate significantly from known weight percentages. The method is based on the assumption that the XRD patterns of pure amorphous components are available which can then be used to extract the corresponding PDFs. Such an approach was able to detect phase separation in ASD exhibiting multiple Tgs (phase separated as per thermal analysis) as well as single Tg (single phase) [47]. Moore et al. also reported that difference plots calculated from linear combinations of PDFs of pure amorphous phases and of co-solidified product could be used to differentiate between phase-separated systems and ASDs [48]. If one of the components of an ASD tends to crystallize very rapidly, it may be difficult to obtain the amorphous reference pattern of this component. In such instances, a chemometric method such as the pure curve resolution method has been used to reconstruct the reference patterns of the component phases of a binary dispersion. In this method, powder XRD patterns of ASDs with different drug loadings are obtained and, from the variance in the data, the reference patterns (pure curves) are extracted statistically [49]. The extracted reference patterns can be compared to measured reference patterns (if available) and used as a semi-quantitative method to estimate the phase composition. If the measured and calculated reference patterns are significantly different or the calculated phase composition does not match the known composition of the dispersion, then the dispersion is miscible to some extent. Additional component or shift of amorphous halo position on the order of ~1° 2θ in extracted pure curves can be considered as indirect evidence of miscibility. The technique has been used to evaluate drug–polymer miscibility behavior in ASD systems, for example PVP

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One major limitation of conventional XRD is the line broadening brought about by crystallite size. The effect is evident from the simulated patterns generated in cellulose Iβ with particle size ranging from 1000 to 20 Å (Fig. 7 [20]). The simulated XRD pattern does not readily reveal whether the material is nanocrystalline or truly amorphous. However, PDF provides more nuanced information in this regard since it can distinctly determine the distances to which molecular ordering exists in the sample. Carbamazepine and indomethacin were rendered amorphous by melt quenching [46]. In Fig. 8, the PDFs from the melt quenched carbamazepine and form III have been overlaid. The excellent agreement after adjusting the standard PDF for finite crystallite size is strong evidence that the local packing in the meltquenched sample is identical to that of form III with an average domain diameter of 4.5 nm. The authors concluded that the melt-quenched carbamazepine formed nanocrystalline domains of carbamazepine III with an average diameter of 4.5 nm. Variations in nanocrystalline structure can also be identified and distinguished from known crystalline polymorphs. Melt-quenched indomethacin was also concluded to be nanocrystalline, but with a local structure that was very different from that of the α- and γ-polymorphs [46]. Recent studies have demonstrated the use of PDF in establishing miscibility of a binary drug–polymer system in ASDs [22]. For phase separated systems, the PDF is assumed to be an incoherent sum of API-API and excipient-excipient interactions [47]. It should be easily reproduced by a linear contribution of reference patterns of the individual phases. In

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Fig. 4. XRD patterns of PVP K-90 (left panel) and PVP K-12 (right panel) equilibrated at various RH values (25 °C). Top to bottom: 5%, 11%, 22%, 53%, 75%, and 94% RH. The XRD pattern of water is provided at the bottom for reference purpose. Reproduced, from reference [33], with permission of Wiley.

Fig. 5. Relationship between crystalline and amorphous phases in terms of ‘thermodynamic’ and ‘kinetic’ disordering processes. The symbols are explained in the text. Tm is the melting temperature, and Tg is the glass transition temperature. Reproduced from reference [35], with permission of Springer.

Fig. 6. PDF pattern of crystalline (‘as is’) and melt-quenched γ-indomethacin. The PDF or G(r) can be thought of as the probability of finding a pair of atoms in the sample as a function of the distance r, between the atoms. The melt-quenched sample quickly becomes “flat” because there is no long range order that is distinct from the average density of the material [44].

Please cite this article as: S. Thakral, et al., Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometry, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.12.013

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As mentioned earlier, unintended amorphization may be induced during pharmaceutical processing steps such as milling and compression [2]. Thus while the ‘as is’ API might be highly crystalline, in the drug product, it could exist in a partially or completely amorphous state. The stresses induced during pharmaceutical processing can result in such transformations. There are numerous examples in the pharmaceutical literature of amorphization of drugs and excipients brought about by milling [52]. However, in many of these systems, milling for unusually long time periods (typically several hours) was necessary to cause amorphization. For example, high energy ball milling of linaprazan, for 47 h (at RT), confirmed amorphization by XRD [53]. Hence, from the perspective of dosage form manufacture, these findings may only be of limited relevance. However, it is important to recognize that since organic compounds are often “soft”, milling even for a very short time period can induce lattice disorder. For example, milling sucrose for 5 s caused a measurable loss in crystallinity [54]. High energy ball milling of griseofulvin for 1 min at RT induced amorphization. Differential scanning calorimetry of this sample, revealed a broad exotherm, reflecting crystallization of the amorphous phase formed [55].

384 385 386 387 388 389 390

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with felodipine, nifedipine or ketoconazole. It was concluded that powder XRD is sensitive to changes in local chemical environments and local structure, which makes it especially useful in elucidating the nature of miscibility in binary mixtures (similar results were reported for IR spectroscopy) [50]. Lyophilized solutions of PVP and dextran were found to be phase separated when the XRD patterns of different compositions were analyzed using PDF analysis, as well as complementary chemometric technique of pure curve resolution method [51].

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Fig. 7. Calculated XRD patterns of various crystallite-sized cellulose Iβ. In the simulations, crystallites of 20, 40, 150, and 1000 Å were used. Adapted from reference [20].

Phase transformation may also be induced by compression. Dexketoprofen trometamol (polymorph ‘A’ or ‘B’), when subjected to direct compression, did not show any transformation and the initial polymorphic form was preserved. However, when subjected to wet granulation by mixing with microcrystalline cellulose, irrespective of the starting polymorphic form of the drug, transformation to the amorphous form was observed. The amorphous form was retained even after drying and compression [56]. The stabilization of the amorphous form can be attributed to the drying conditions, coupled with the excipients acting as crystallization inhibitors. At compression pressures relevant to commercial tablet manufacture, partial amorphization was observed in tablets of theophylline anhydrate, nitrofurantoin, and amlodipine besylate. The extent of amorphization increased as a function of compression pressure and was most pronounced in the outer surface regions. The technique of grazing incidence X-ray diffraction was used to obtain semiquantitative information of the extent of amorphization as a function of tablet depth [57]. The reverse transformation, i.e. amorphous ➔ crystalline drug transition is extensively reported in the literature. Compression of freeze dried amorphous sucrose, at pressures ranging from 74 to 665 MPa, facilitated the formation of critical nuclei thereby decreasing the induction time for crystallization and lowering the crystallization temperature [58]. Tablets of amorphous spray dried dispersion of ibipinabant, when coated with aqueous moisture barrier film coat, exhibited increased level of crystallinity due to the exposure of the amorphous matrix to water vapor at elevated temperature [59]. At modest compaction pressures ranging from 27.4 to 137.5 MPa, crystallization of amorphous celecoxib was observed. Even after the drug was formulated into a solid dispersion, the compression induced crystallization could not be prevented [60]. In compounds which are so readily prone to crystallization, preparing tablet dosage forms of the amorphous drug can be practically challenging. The compression-induced crystallization propensity of amorphous indomethacin was investigated at different compression pressures [25]. Two-dimensional XRD enabled the study of spatial distribution of crystallization. At low compression pressures (10 and 25 MPa), the extent of crystallization was much higher at the radial surface, and the tablet core was substantially amorphous (Fig. 9; [25]). However as the compression pressure was increased, there was a pronounced reduction in the crystallization gradient. Trehalose dihydrate crystallization, following storage of amorphous trehalose tablets at 65% RH (RT), was investigated by several techniques. In glancing angle diffractometry, the penetration depth of Xrays was modulated by the incident angle. This approach enabled the analyses of intact tablets, though the technique suffers from a ‘surface

E

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Fig. 8. Comparison of PDFs from the melt-quenched sample (green) and carbamazepine III (blue), modified to have domain size of 4.5 nm. Reproduced from reference [46], with permission of Royal Society of Chemistry.

Fig. 9. Profiling of indomethacin crystallization across the radial surface in split tablets. Amorphous indomethacin tablets (8 mm diameter) were compressed at different pressures (10 to 100 MPa) in an unlubricated die and stored at 35 °C for 24 h [25]. Tablets were split into two halves, and crystallization was monitored as a function of distance, in the radial direction (inset). Indomethacin crystallization is attributed to both the compression pressure and the die wall friction. The “increased” crystallization on the radial surface is due to the die wall friction. Reprinted with permission from reference [25], copyright (2015) American Chemical Society.

Please cite this article as: S. Thakral, et al., Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometry, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.12.013

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448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465

xcr ¼

472

R

R

470 471

where p and q are proportionality constants. Within identical regions of reciprocal space, the diffracted intensity from a material will be independent of its state of order. Thus the integrated intensity diffracted by a completely (100%) crystalline sample will be the same as that diffracted by a completely (100%) amorphous sample [65]. If this assumption is valid, all samples with different levels of amorphous content can be normalized to the same integrated intensity of either 100%

N C O

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Ic  100 Ic þ q =p I a

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A major limitation and challenge with amorphous pharmaceuticals is their propensity for spontaneous crystallization. While the crystallization propensity tends to be pronounced in the supercooled state, it can also happen in the glassy state and at temperatures far below the glass transition temperature (Tg) [62]. An added potential complication is the tendency of amorphous drugs to sorb water which will lower the Tg (plasticization) and cause destabilization. Numerous factors including the sample history and the storage conditions will influence the amorphous → crystalline transition. Once nucleation is initiated (say during the preparation of the amorphous phase), crystallization may progress during product storage. Therefore, quantifying low levels of crystallinity (first evidence of crystallization) is of great practical relevance. X-ray diffractometry, alone or in combination with other techniques, is useful for determining crystallization onset and for studying crystallization kinetics of amorphous APIs. The method pioneered by Hermans and Weidinger is widely used by the pharmaceutical community [63,64]. When an analyte occurs in both the crystalline and amorphous states, the experimentally measured crystalline (Ic) and amorphous (Ia) intensities are proportional to the crystalline (xc), and amorphous (xa) fractions of the sample. The procedure is based on the assumption that it is possible to demarcate and measure Ic and Ia from the powder pattern. Hence, degree of crystallinity (expressed as percentage) of a sample can be given by

O

443

Nunes et al. have experimentally established that the ratio of the two proportionality constants, p/q, was close to one (Fig. 11; [66]. They monitored the crystallization of sucrose in a synchrotron beamline. The use of a two-dimensional area detector, coupled with a unique algorithm to separate and quantify amorphous (Ia) and crystalline (Ic) intensity contributions from the X-ray patterns, led to a detection limit of 0.2% w/w crystallinity. Significant efforts have also been directed towards the study and prediction of crystallization kinetics of amorphous drugs. XRD, either alone or in combination with other techniques, has been used to evaluate crystallization kinetics usually in supercooled APIs. Surana and Suryanarayanan monitored sucrose crystallization as a function of temperature and water vapor pressure [67]. Crystallization was facilitated, either by increasing temperature (~ 40 °C above Tg) or by increasing the water vapor pressure (65, 74, and 80% RH at 27 °C) in the XRD chamber. In a recent study, Kothari et al. studied crystallization kinetics of amorphous nifedipine and griseofulvin in the supercooled as well as glassy states. A laboratory powder X-ray diffractometer was adequate for monitoring crystallization above Tg while a synchrotron source enabled measurement of low levels of crystallization (0.5%) in the glassy state (Fig. 12; [68]). The ability of PDF to quantify mixed amorphous and crystalline phases from controlled recrystallization of cryomilled sulfamerazine was demonstrated by Davis et al. [69] In a more recent study, amorphous lactose was prepared by lyophilization or melt quenching and its properties were compared with that of commercially available spray-dried lactose (Flowlac® 100) [70]. Fig. 13a depicts the overlay of PDFs of all three amorphous lactose samples. As evident from the figure, the PDF pattern of melt quenched sample shows subtle differences from the patterns of spray dried and lyophilized samples. In an effort to characterize the structural development leading to crystallization, PDF measurements were taken incrementally as the product was aged at 40 °C/75% RH. Plots of the crystalline phase fraction as a function of time (Fig. 13b), indicates that the melt quenched sample remained stable while the others readily crystallized to the stable α-monohydrate structure. A higher degree of intermolecular ordering was found to correlate with instability in samples which crystallized. Interestingly, prior to bulk crystallization, a separate precursor structure was formed. Such studies could be invaluable towards elucidating the mechanisms

R O

6. Quantification using XRD

Ic  100: Ic þ Ia 476

T

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xcr ¼

P

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438 439

amorphous or 100% crystalline sample. Thus the ratio, q/p, can be con- 473 sidered to be equal to one and the equation simplifies to: 474

bias’ (Fig. 10a). In a second approach, the tablets were split and subjected to microdiffractometry. The surface had crystalized completely in 5 days, while it took 30 days for the crystallization to be complete in the tablet core (Fig. 10b). Though this is a “destructive” technique, it provided comprehensive and unbiased depth profiling information [61].

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Fig. 10. Extent of trehalose dihydrate crystallization, as a function of depth (surface to core; inset) in amorphous trehalose tablets stored at 65% RH at RT [61]. a) Results of analyses of intact tablets by glancing angle X-ray diffractometry. The extent of crystallization in three different layers as a function of time. b) Results of analyses of split tablets by microdiffractometry. For the sake of clarity, only the results of the surface and core are presented. Complete crystallization on the surface was observed in 5 days but it took 30 days for the core to fully crystallize. Adapted with permission from reference [61], copyright (2015) American Chemical Society.

Please cite this article as: S. Thakral, et al., Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometry, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.12.013

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531 532 533 534 535 536 537 538 539 540

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fraction of the drug in several tacrolimus ASD products. They used truncated XRD data from 8.3 to 11.4° 2θ (due to the absence of excipients peaks and presence of the most intense crystalline drug peaks) and applied multivariate methods, PLS and PC analysis. The developed models were reasonably accurate and could quantitate up to 10% of crystalline tacrolimus even when drug to excipients ratio was as high as 1:49. As compared to PLS method, the errors were higher with the PC model predicted values [76]. Recently, second harmonic generation microscopy was coupled with synchrotron XRD to detect 100 ppm crystalline ritonavir in an amorphous HPMC matrix. This is currently the most sensitive technique for detecting drug crystallinity in a complex matrix [77]. Comparison of crystallization kinetics of drug from ASD prepared using different polymers is a useful polymer screening tool. Wegiel et al. used XRD to monitor crystallization kinetics of resveratrol in different polymers. In order to generate calibration curves, ASD prepared by rotary evaporation were spiked with crystalline drug. Drug - polymer interactions were studied by IR spectroscopy. The polymers forming weaker hydrogen bond interactions with resveratrol were less effective crystallization inhibitors [78]. In nifedipine solid dispersions with different polymers, hydrogen bond formation between nifedipine and PVP imparted improved physical stability than in HPMCAS dispersions with weaker van der Waals interactions [79]. In ketoconazole-polymer dispersions, acid–base interaction between drug and poly-(acrylicacid) led to considerable delay in crystallization onset as compared to the hydrogen bonding interactions of drug with PHEMA (poly(2hydroxyethyl methacrylate) or dipole-dipole interactions with PVP [80].

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underpinning crystallization processes and to better understand and predict sample stability by observing the nanocrystalline domains which first nucleate during crystallization. Our discussion so far was restricted to crystallization in single component systems. As pointed out earlier, ASD are designed to be homogeneous drug–polymer mixtures. Though formulation as ASD is a promising strategy to delay drug crystallization, the physical stability of the drug during storage is not guaranteed, since drug crystallization can occur even at temperatures well below the Tg of the system [71]. Numerous environmental, formulation, and processing factors may influence the stability and hence the actual performance of the solid dispersion. For example, the API may tend to crystallize due to poor formulation (high drug loading, improper excipient selection) and/or when subjected to improper storage (exposed to high humidity/temperature conditions) [72]. API crystallization either during processing or during the shelf-life of the pharmaceutical product can have serious adverse effects on product performance [73]. In order to quantify the crystalline content in an amorphous solid dispersion using XRD, the classic method based on estimation of integrated intensity counts for the characteristic peak/s is conventionally useful. Some recent studies are based on developing calibration curves by spiking the drug–polymer ASD with known crystalline content. Statistical approaches such as partial least square (PLS) and principal component (PC) analysis have been applied to improve quantification by X-ray diffractometry [74,75]. Rahman et al. developed XRD based chemometric method to quantitate the amorphous and crystalline

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Fig. 11. Plot of amorphous (Ia) versus crystalline (Ic) intensity during isothermal crystallization of amorphous sucrose. The slope of regression lines provided the value of the proportionality constant q/p. (0.995 ± 0.026; mean ± standard deviation; n = 5). Reproduced from reference [66], with permission of Springer.

Fig. 13. (a) PDF patterns of amorphous lactose prepared by different methods. The spraydried lactose was commercially available (details in the text). (b) Crystallinity of amorphous lactose following storage at 40 °C/75% RH. Adapted with permission from reference [70]. Copyright (2015) American Chemical Society.

Fig. 12. (a) Synchrotron XRD patterns in amorphous nifedipine at 40 °C as a function of time revealing progressive crystallization from the sample. (b) Percentage crystallinity in nifedipine as a function of time (mean ± SD; n = 3). Reprinted with permission from reference [68], copyright (2014) American Chemical Society.

Please cite this article as: S. Thakral, et al., Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometry, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.12.013

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Fig. 14. The design space for physically stable ASD (no crystallization based on XRD), with desired target shelf-life. XRD was the basis for detecting drug crystallization. Reproduced from reference [81], with permission of Springer.

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Recent developments in total scattering PDF may be useful for characterizing disordered pharmaceuticals. Computed tomography PDF is a technique for spatially mapping the local structure in three dimensional objects and has been used to characterize catalysts [84] and batteries [85]. The technique can be extended for characterizing drugs in intact dosage forms such as tablets, and in complex drug delivery systems such as implants with amorphous/nanocrystalline components. Additionally, thin film PDF can be used for analyzing thin layers of material on a substrate and could reasonably be applied to amorphous pharmaceutical thin films [86,87]. These techniques require both high energy and high flux radiation.

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While powder X-ray diffractometry is recognized as a very powerful technique for the identification and quantification of crystalline phases, it has until recently been of limited utility in characterizing amorphous pharmaceuticals. It is now emerging as a powerful technique to gain structural insights into amorphous and nanocrystalline materials. This has become possible through developments in pair distribution function analysis of X-ray diffractograms collected to high angles and high momentum transfers. Instrumental advances, including high energy, high flux sources and the widespread availability of two dimensional detectors, have dramatically reduced both data collection times and preferred orientation errors. XRD finds widespread use to detect drug crystallization in a variety of complex matrices and in the presence of numerous excipients. The ability to characterize such materials makes formulating poorly water soluble compounds in the amorphous state a viable avenue to enhance their oral bioavailability.

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Acknowledgements

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We thank Simon Billinge, Timothy Fawcett, Thomas Blanton and Soorya Kabekkodu for their help. NKT was sponsored by the Lilly Innovation Fellowship Award and RS was partially supported by the William and Mildred Peters Endowment Fund.

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[1] N. Shah, H. Sandhu, D.S. Choi, H. Chokshi, A.W. Malick, Amorphous solid dispersions, Theory and Practice, Springer, New York, 2014. [2] T.P. Schachtschneider, Phase transformations and stabilization of metastable states of molecular crystals under mechanical activation, Solid State Ionics 101 (1997) 851–856. [3] C.A. Lipinski, Drug-like properties and the causes of poor solubility and poor permeability, J. Pharmacol. Toxicol. Methods 44 (2000) 235–249. [4] N.J. Babu, A. Nangia, Solubility advantage of amorphous drugs and pharmaceutical cocrystals, Cryst. Growth Des. 11 (2011) 2662–2679. [5] B.C. Hancock, M. Parks, What is the true solubility advantage for amorphous pharmaceuticals? Pharm. Res. 17 (2000) 397–404. [6] S.B. Murdande, M.J. Pikal, R.M. Shanker, R.H. Bogner, Solubility advantage of amorphous pharmaceuticals: II. Application of quantitative thermodynamic relationships for prediction of solubility enhancement in structurally diverse insoluble pharmaceuticals, Pharm. Res. 27 (2010) 2704–2714. [7] T. Vasconcelos, B. Sarmento, P. Costa, Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs, Drug Discov. Today 12 (2007) 1068–1075. [8] G. Zografi, A. Newman, Introduction to amorphous solid dispersions, in: A. Newman (Ed.), Pharmaceutical Amorphous Solid Dispersions, John Wiley & Sons, New Jersey 2015, pp. 1–42. [9] P.C. Sheen, S.I. Kim, J.J. Petillo, A. Serajuddin, Bioavailability of a poorly water-soluble drug from tablet and solid dispersion in humans, J. Pharm. Sci. 80 (1991) 712–714. [10] M. Kennedy, J. Hu, P. Gao, L. Li, A. Ali-Reynolds, B. Chal, V. Gupta, C. Ma, N. Mahajan, A. Akrami, S. Surapaneni, Enhanced bioavailability of a poorly soluble VR1 antagonist using an amorphous solid dispersion approach: a case study, Mol. Pharm. 5 (2008) 981–993. [11] Y. Kawabata, K. Wada, M. Nakatani, S. Yamada, S. Onoue, Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications, Int. J. Pharm. 420 (2011) 1–10. [12] P. Ke, S. Qi, G. Sadowski, D. Ouyang, Solid dispersion — a pragmatic method to improve the bioavailability of poorly soluble drugs, in: D. Ouyang, S.C. Smith (Eds.), Computational Pharmaceutics, John Wiley & Sons, West Sussex 2015, pp. 81–97. [13] A. Siddiqui, Z. Rahman, S.R. Khan, D. Awotwe-Otoo, M.A. Khan, Root cause evaluation of particulates in the lyophilized indomethacin sodium trihydrate plug for parenteral administration, Int. J. Pharm. 473 (2014) 545–551. [14] J.F. Carpenter, B.S. Chang, Lyophilization of protein pharmaceuticals, in: K.E. Avis, V.L. Wu (Eds.), Biopharmaceutical Manufacturing, Processing, and Preservation, Interpharm Press, Buffalo Grove, IL 1996, pp. 199–264. [15] J.F. Carpenter, M.J. Pikal, B.S. Chang, T.W. Randolph, Rational design of stable lyophilized protein formulations: some practical advice, Pharm. Res. 14 (1997) 969–975. [16] P. Sundaramurthi, R. Suryanarayanan, Trehalose crystallization during freezedrying: implications on lyoprotection, J. Phys. Chem. Lett. 1 (2009) 510–514. [17] P. Sundaramurthi, R. Suryanarayanan, Calorimetry and complementary techniques to characterize frozen and freeze-dried systems, Adv. Drug Deliv. Rev. 64 (2012) 384–395. [18] The United States Pharmacopeia 38/The National Formulary 33, United States Pharmacopeial Convention, Rockville, MD, 2015. [19] NIST, http://www.nist.gov/mml/mmsd/sustainable-materials/diffraction-metrology.cfm (Accessed) October 12, 2015.

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Greco et al. used XRD to monitor the crystallization onset time in a spray dried HPMC phthalate solid drug dispersion following exposure to elevated temperature and water vapor pressure [81]. In the glassy state, the crystallization onset time (plotted on log scale; log toc) varied linearly with Tg/T. The crystallization data obtained over a short time period (3 months) could be extrapolated to longer periods (N 15 months). This enabled the prediction of the Tg/T values for the desired shelf-life of the product. Based on storage temperature and RH as the “stress” factors, a design space for the desired target shelf-life was proposed (Fig. 14). One unique feature of the model was its ability to predict long-term stability based on short-term assessment. XRD has also been used to monitor crystallization, both of amorphous ‘as is’ drug, and drug in ASDs following exposure to aqueous media. Van Eerdenbrugh et al. induced precipitation of amorphous drug from supersaturated solution, by mixing concentrated API solutions in DMSO with an aqueous buffer in a capillary, and monitored in situ crystallization using synchrotron radiation. In another experimental setup, buffer solution was added to melt quenched amorphous film of API and crystallization was monitored using polarized light microscopy. When ~ 50 APIs were tested, the crystallization behavior was (i) essentially independent of the technique, (ii) dictated by API properties (iii) varied significantly, ranging from immediate and complete crystallization to no observable crystallization over experimental time scales. As a result, the compounds were classified into rapid, intermediate, and slow crystallizers [82]. XRD has also been used to study the effectiveness of polymer in maintaining drug supersaturation in solution. Alonzo et al. monitored concentration-time profiles during dissolution of the model amorphous compounds, felodipine and indomethacin in solutions of PVP and HPMC [83]. In the absence of polymer, upon exposure to the dissolution medium, a small extent of drug supersaturation was generated followed by rapid drug crystallization. The presence of polymer in solution led to dramatic reduction in the crystallization tendency and generation of supersaturated drug solutions.

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Please cite this article as: S. Thakral, et al., Recent advances in the characterization of amorphous pharmaceuticals by X-ray diffractometry, Adv. Drug Deliv. Rev. (2015), http://dx.doi.org/10.1016/j.addr.2015.12.013

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Zografi, Assessing the performance of amorphous solid dispersions, J. Pharm. Sci. 101 (2012) 1355–1377. [74] A.C. Rumondor, L.S. Taylor, Application of partial least-squares (PLS) modeling in quantifying drug crystallinity in amorphous solid dispersions, Int. J. Pharm. 398 (2010) 155–160. [75] A. Siddiqui, Z. Rahman, S. Bykadi, M.A. Khan, Chemometric methods for the quantification of crystalline tacrolimus in solid dispersion by powder X-ray diffractrometry, J. Pharm. Sci. 103 (2014) 2819–2828. [76] Z. Rahman, S. Bykadi, A. Siddiqui, M.A. Khan, Comparison of X-ray powder diffraction and solid-state nuclear magnetic resonance in estimating crystalline fraction of tacrolimus in sustained-release amorphous solid dispersion and development of discriminating dissolution method, J. Pharm. Sci. 104 (2015) 1777–1786. [77] J.A. Newman, P.D. Schmitt, S.J. Toth, F. Deng, S. Zhang, G.J. Simpson, Parts per million powder X-ray diffraction, Anal. Chem. (2015) published online. [78] L.A. Wegiel, L.J. Mauer, K.J. Edgar, L.S. Taylor, Crystallization of amorphous solid dispersions of resveratrol during preparation and storage — impact of different polymers, J. Pharm. Sci. 102 (2013) 171–184. [79] K. Kothari, V. Ragoonanan, R. Suryanarayanan, The role of drug–polymer hydrogen bonding interactions on the molecular mobility and physical stability of nifedipine solid dispersions, Mol. Pharm. 12 (2015) 162–170. [80] P. Mistry, S. Mohapatra, T. Gopinath, F.G. Vogt, R. Suryanarayanan, Role of the strength of drug–polymer interactions on the molecular mobility and crystallization inhibition in ketoconazole solid dispersions, Mol. Pharm. 12 (2015) 3339–3350. [81] S. Greco, J.R. Authelin, C. Leveder, A. Segalini, A practical method to predict physical stability of amorphous solid dispersions, Pharm. Res. 29 (2012) 2792–2805. [82] B. Van Eerdenbrugh, S. Raina, Y.L. Hsieh, P. Augustijns, L.S. Taylor, Classification of the crystallization behavior of amorphous active pharmaceutical ingredients in aqueous environments, Pharm. Res. 31 (2014) 969–982. [83] D.E. Alonzo, G.G. Zhang, D. Zhou, Y. Gao, L.S. Taylor, Understanding the behavior of amorphous pharmaceutical systems during dissolution, Pharm. Res. 27 (2010) 608–618.

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