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Solid-State Spectroscopic Investigation of Molecular Interactions between Clofazimine and Hypromellose Phthalate in Amorphous Solid Dispersions Haichen Nie,†,‡ Yongchao Su,*,§ Mingtao Zhang,† Yang Song,†,⊥ Anthony Leone,§ Lynne S. Taylor,† Patrick J. Marsac,¶ Tonglei Li,† and Stephen R. Byrn*,† †

Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States ‡ Formulation Sciences, Teva Pharmaceuticals, 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States § Merck Research Laboratories, 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States ⊥ Global DMPK, Takeda Pharmaceutical Inc., 10410 Science Center Drive, San Diego, California 92121, United States ¶ Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, Kentucky 40536, United States S Supporting Information *

ABSTRACT: It has been technically challenging to specify the detailed molecular interactions and binding motif between drugs and polymeric inhibitors in the solid state. To further investigate drug−polymer interactions from a molecular perspective, a solid dispersion of clofazimine (CLF) and hypromellose phthalate (HPMCP), with reported superior amorphous drug loading capacity and physical stability, was selected as a model system. The CLF−HPMCP interactions in solid dispersions were investigated by various solid state spectroscopic methods including ultraviolet−visible (UV−vis), infrared (IR), and solid-state NMR (ssNMR) spectroscopy. Significant spectral changes suggest that protonated CLF is ionically bonded to the carboxylate from the phthalyl substituents of HPMCP. In addition, multivariate analysis of spectra was applied to optimize the concentration of polymeric inhibitor used to formulate the amorphous solid dispersions. Most interestingly, proton transfer between CLF and carboxylic acid was experimentally investigated from 2D 1H−1H homonuclear double quantum NMR spectra by utilizing the ultrafast magic-angle spinning (MAS) technique. The molecular interaction pattern and the critical bonding structure in CLF−HPMCP dispersions were further delineated by successfully correlating ssNMR findings with quantum chemistry calculations. These high-resolution investigations provide critical structural information on active pharmaceutical ingredient−polymer interaction, which can be useful for rational selection of appropriate polymeric carriers, which are effective crystallization inhibitors for amorphous drugs. KEYWORDS: amorphous, solid dispersion, drug−polymer interactions, acid−base interaction, solid-state NMR, ultrafast MAS, principal components analysis

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INTRODUCTION Amorphous solid dispersion (ASD) formulations, where the active pharmaceutical ingredient (API) is molecularly dispersed in a polymeric matrix, are widely applied to improve bioavailability for poorly water-soluble pharmaceutical entities.1−5 However, maintaining the amorphous state of drug substances in ASDs is a challenge, whereby intermolecular interactions formed between the API molecule and functional groups of the polymer are thought to be of critical importance.6−10 For instance, it has been demonstrated that polyvinylpyrrolidone (PVP) forms strong intermolecular interactions with resveratrol in the dispersion, which lead to satisfactory physical stability at stressed condition,11 while PVP can also show insufficient inhibitory effects on itraconazole © XXXX American Chemical Society

crystallization due to the absence of drug−polymer interactions.12 Typically, stronger drug−polymer intermolecular interactions can more effectively disrupt molecular selfassembly of the API in the dispersion and therefore lead to a relatively stable ASD system with a high drug loading. For example, formation of strong association between clofazimine (CLF) and hypromellose phthalate (HPMCP) leads to an ASD system with superior drug loading capacity and physical stability.13 Acid−base interaction, an electrostatic interaction Received: August 10, 2016 Revised: September 19, 2016 Accepted: September 21, 2016

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DOI: 10.1021/acs.molpharmaceut.6b00740 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Molecular Pharmaceutics

critical structure elements of the CLF−HPMCP complex. Moreover, another goal of this study was to determine an optimized ratio of drug and polymer by using multivariate analysis of spectra. The findings of this research can serve as a precedent demonstrating the utility of comprehensive spectroscopic investigations on drug and polymer interactions, which is critical for the rational design of innovative ASD formulations.

formed by ionized molecules, is perhaps the strongest intermolecular association possible between an API and polymeric carrier. The formations of such strong intermolecular interactions in dispersions are generally favorable especially for high-dose formulations.14−19 For instance, ASD systems of lapatinib with ionizable polymers illustrated the utility of acid− base interactions in formulations as a strategy to enhance the drug loading capacity.20 Hence, understanding the molecular interaction patterns between API and polymeric carriers is of significance to efficiently design robust formulations of ASDs with satisfactory physical stability at minimal polymer concentrations avoiding the reliance on the empirical polymer screening process. However, molecular details of drug−polymer interaction patterns are still unclear due to the challenges of identifying the interaction type, functional group involvement, and the binding motif in amorphous materials.21 Although our previous research provided an improved understanding of intermolecular interaction patterns between CLF and HPMCP in a nonpolar solvent system prior to forming the solid dispersion,13 knowledge about CLF− HPMCP interactions in the solid state is still limited, which necessitates the employment of comprehensive solid state spectroscopic investigations. Infrared (IR) spectroscopic analysis, a powerful tool to select the appropriate polymer for ASD formulations, can be used to monitor drug−polymer interactions by evaluating the vibrational changes of involved functional group.22−24 Ultraviolet−visible (UV−vis) spectroscopy is a useful method to estimate the electronic property changes of molecules containing conjugated structures.25 In the past decade, solid-state NMR (ssNMR) has been successfully applied to provide atomic-level structural insights of intra- and intermolecular interactions in ASDs.26−32 The molecular proximity between API and polymer has been experimentally detected in various dipolar experiments utilizing homo- and heteronuclear correlation. For example, 2D 1H−1H correlation experiments have observed cross peaks between the −OH and aliphatic groups of diflunisal and aromatic groups of PVP, suggesting their close contact (∼3 Å).30 Moreover, the fast magic angle spinning (MAS) NMR technology enables the 1H detection that could otherwise be impossible for ssNMR. In recent years, the advances of sample spinning at ultrafast frequency, that is, > 60 kHz, can largely improve spectral resolution by averaging the 1H−1H homonuclear dipolar interaction to a greater extent. The gained resolution further minimizes the sample amount to approximately 5 mg for obtaining 1H spectra. This allows a more extensive application of the 1H-detected multidimensional correlation to determine convoluted structures.33−35 The improved resolution and intensity under ultrafast MAS spinning also make 2D 1Hdetected experiments more applicable for probing detailed structural information on natural-abundant organic solids.30,36 In the present research, taking advantage of aforementioned spectroscopic analyses, the goal was to probe the solid-state interaction patterns of CLF and HPMCP dispersions at a molecular level and to further elucidate the underlying reaction mechanism. On the basis of our previous research about ionpair formation of CLF and HPMCP in a nonpolar solvent system, we herein hypothesized the presence of acid−base interactions in CLF−HPMCP solid dispersions and focused on obtaining direct spectroscopic evidence of such an interaction. An objective of particular interest was to combine the molecular-level results from ssNMR and computational chemistry to determine the structure or, at a minimum, the

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EXPERIMENTAL SECTION Materials. CLF (Figure 1A) in crystalline form was purchased from Sigma-Aldrich (St. Louis, MO). HPMCP

Figure 1. Chemical structures of CLF (A) and HPMCP (B) whereby the weight percentages of substituents are listed and NPA of charges for CLF (C).

(HP-55, Figure 1B) was generously provided by Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). Dichloromethane (ChromAR grade) was obtained from Mallinckrodt Baker, Inc. (Paris Kentucky). Ethanol (200 proof) was supplied by Pharmaco Products, Inc. (Brookfield, CT). Both CLF and HPMCP were individually stored in desiccators with calcium sulfate (W.A. Hammond Drierite Co. Ltd., Xenia, OH) for at least 7 days at 25 °C. The melt-quenching method was employed to prepare a neat reference sample of amorphous CLF: the crystalline form of CLF was placed on a THMS600 temperature controlled hot-stage (LINKAM scientific, Surrey, UK) at 220 °C for approximately 10 min and then quenchcooled by liquid nitrogen. Preparation of Solid Dispersion. Both CLF and HPMCP at the desired dry weight ratios were fully dissolved (visually inspected, sonication was applied as needed) in a 1:1 (v/v) solvent mixture of dichloromethane and ethanol to form B


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Figure 2. PXRD for CLF−HPMCP dispersion systems (weight ratio of CLF to HPMCP is listed in legend).

(Billerica, MA) equipped with global IR source, KBr beam splitter, and DTGS detector. A scan range from 1000−4000 cm−1 was set with 128 scans coadded and 4 cm−1 resolution. A vacuum was applied to the sample and detector compartments to minimize the interference from moisture present in air. IR spectra of pure CLF or HPMCP were collected by the same method. Spectra were virtually inspected by OPUS software v7 (Bruker Optics, Ettlingen, Germany). PCA of infrared spectra was processed using SIMCA v13 (Umetrics AB, Umeå, Sweden). Solid-State NMR Spectroscopy (ssNMR). All ssNMR spectra were acquired on a Bruker HD Advance III tripleresonance spectrometer operating at 1H and 13C resonance frequency of 400 and 100 MHz, respectively. All 13C experiments were carried out by using a Bruker 4.0 mm triple resonance HXY MAS probe tuned to 1H and 13C doubleresonance mode, as previously described.39 Approximately 90 mg of ASD powder was packed into 4.0 mm MAS zirconium rotors for each experiment. Sample temperature was maintained at 293 K using a BCU cooling system. One-dimensional (1D) 13C spectra were acquired using the cross-polarization magic angle spinning (CP-MAS) experiment under a spinning frequency of 12 kHz. 1H to 13C cross-polarization was applied with a 1.5 ms contact time and a linear ramp on the 1H channel and constant field on the 13C channel. An 83 kHz SPINAL 1H decoupling was used during acquisition. 1 H-detected experiments were carried out using an H/F/X ultrafast spinning probe on approximately 4 mg of sample packed into a Bruker 1.3 mm rotor spinning at 60 kHz and at a proton frequency of 400 MHz. The cooling gas streams from BCU-II at 253 K were streamed to control the sample temperature. 2D 1H−1H dipolar double quantum (DQ) correlation spectra were recorded using back-to-back (BABA) scheme.40 This experiment employs a rotor-synchronized pulse sequence, which excites DQ coherence from 1H homonuclear dipolar coupling in the excitation period and reconverts to single quantum coherence for detection. For all 2D experiments, the 1 H 90° pulses during the excitation and reconversion blocks were 1.2 μs. Other experiment parameters include 32 scan signal average with a 2.5 s recycle delay, one rotor cycle BABA recoupling, 9.1 ms maximum evolution time

homogeneous solutions. These uniform single-phase solutions were then employed to prepare solid dispersions by using rotary evaporation or spin coating to remove the solvents. For rotary evaporation, dichloromethane and ethanol were removed by a rotary-evaporator (Buchi, New Castle, DE) under vacuum and submersed into a water bath maintained at a constant temperature (∼50 °C) for 2−3 min. Dispersions of CLF− HPMCP were afterward exposed to a vacuum at room temperature for at least 24 h to further remove any residual solvents in the powder. Dispersions prepared by spin coating were used for ultraviolet−visible spectroscopic and infrared spectroscopic analysis. Several drops of the solution were placed either on a quartz microscope slide or on a barium fluoride (BaF2) infrared substrate (VWR, Radnor, PA). Spin coating was performed using a KW-4A spin coater (Chemat Technology Inc., Northridge, CA) with a rate of 200 rpm for 20 s (for quartz slides) and 100 rpm for 10 s (for barium fluoride substrate) at ambient temperature to readily remove solvents.37 Powder X-ray Diffraction (PXRD). The XRD patterns of CLF−HPMCP solid dispersions prepared by rotary evaporation were collected on a Panalytical X’Pert pro X-ray diffractometer (PANalytical Inc., Westborough, MA) with Cu Kα radiation of 1.5406 Å in transmission mode. Measurements were conducted at ambient conditions in transmission geometry with 2θ ranging from 2−40° using a 0.0167° step size. The voltage and the current of the generator were set to 45 kV and 40 mA, respectively. PXRD data were processed by Panalytical X’Pert Data Viewer (version 1.5) software. Solid-State Ultraviolet−Visible (UV−vis) spectroscopy. A Cary 300 Bio UV spectrometer coupled with WinUV software (Varian Inc., Palo Alto, CA) was employed to analyze dispersions of CLF and HPMCP spin-coated onto quartz slides. Data were collected over the wavelength range from 200−800 nm, while the spectral region of 370−600 nm was used for subsequent analyses. Multivariate analysis software SIMCA v13 (Umetrics AB, Umeå, Sweden) was applied for principal components analysis (PCA). Standard normal variate transformation (SNV) was employed to preprocess the spectra.38 Infrared (IR) Spectroscopy. IR spectra of CLF and HPMCP dispersions were obtained in transmission mode using a Bruker Optics IR IFS 66 V/S spectrophotometer C


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also can become negatively charged by proton donation, subsequently forming an ionic interaction. Considering the pKa values of CLF (8.5)51 and HPMCP (∼3),20 further support for the formation of an acid−base interaction can be established on the basis of the salt formation rule which indicates that proton transfer likely occurs between acidic/basic components when the ΔpKa value (pKa basic component−pKa acidic component) is greater than 2−3.52−55 Therefore, spectroscopic evidence of ionic bonding between negatively charged phthalate and protonated CLF was sought as described further. Solid-State Spectroscopic Investigation of Drug− Polymer Interactions. UV−vis Spectroscopy. Pure CLF presents with a red color in both crystalline and amorphous forms, while an apparent color change from red to dark purple can be visually inspected when CLF is formulated with HPMCP as a solid dispersion (Figure S1). This color-change phenomenon also can be observed for solvent evaporated mixtures of CLF and glacial acetic acid/formic acid. Interestingly, no color change can be detected for CLF solid dispersions prepared with polymers that lack of carboxylic acid group (e.g., PVP/VA or HPMC). These interesting findings further suggest that the carboxylic acid group from phthalyl on HPMCP is the key functional group that interacts with CLF in solid dispersions. Furthermore, significant differences of the UV−vis spectra between the pure CLF and CLF−HPMCP dispersions were observed in the visible wavelength range. To be specific, CLF alone shows a broad peak centered at 450 nm. This peak gradually bathochromically shifted to 487 nm when CLF− HPMCP dispersions were prepared with different weight ratios (Figure 3A). It is important to point out that the HPMCP alone has no visible absorption peak in this spectral region. The color-change phenomenon and the corresponding red-shifted visible absorption spectra of CLF−HPMCP dispersions are directly caused by the impact of electrostatic interactions on chromophore of the drug molecule.56−58 In this case, Nα of the imine group is located at the π-conjugated riminophenazine core, which is the chromophore of the CLF. The proton of polymer carboxylic acid group transfers to the Nα, which yields a carboxylate group and a protonated imine group. Therefore, protonation of the riminophenazine core leads to electron density changes in the conjugated chromophore that result in the obvious color-change and red-shifted visible spectra.59,60 To further quantitatively investigate the effect of HPMCP on this bathochromic shift, spectra of dispersions with CLF/ HPMCP (w/w) ratios ranging from 1:0.1−1:2 were subjected to principal components analysis (PCA). The first principal component (PC1) captured over 97% of the spectral variation in the wavelength range 380−600 nm. A principal component score is the projection of an observation, that is, UV−vis spectrum, as a single object in principal component space. In this case, PC1 scores are plotted against HPMCP/CLF (w/w) to probe the best HPMCP content in the CLF solid dispersion formulations (Figure 3B). On the basis of Figure 3, panels A and B, no significant red-shift was observed for the peak centered at 450 nm when the CLF/HPMCP (w/w) ratio was less than 1:0.5, which indicated that an insufficient amount of HPMCP in these dispersions may lead to only limited protonation of CLF, which is undetectable in UV−vis spectroscopy. On the other hand, the wavelength of the broad peak has the largest bathochromic shift (∼37 nm) when the weight ratio of CLF to HPMCP reaches 1:1.5, which suggests total protonation of the interaction center. The

in indirect dimension and 12.9 ms during direct acquisition period, and a 16-step phase cycle. Glycine was used as an external 13C chemical shift reference by setting the carbonyl 13C peak at 176.49 ppm. 1H chemical shifts are referenced by setting the single 1H resonance of adamantane at 1.6 ppm on the TMS scale. All spectra were recorded and processed in TopSpin 3.5. Computational Methods. The density functional theory (DFT) based calculations for both pure CLF and its complexes were performed using Gaussian 09 software package41 with the DFT level of the hybrid B3PW91 function and 6-311+ +g(2d,2p) basis set.42−44 By using the previously published CLF structure as a starting point,45 optimizations were conducted in the gas state without any geometrical constraints as approximation to the structure in the amorphous solid state. No imaginary frequency was obtained in the output of frequency analysis of each system. The gauge-independent atomic orbital (GIAO) method was applied herein for NMR chemical shifts calculations.46

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RESULTS AND DISCUSSION Amorphous Drug Loading and Chemical Features. The XRD patterns of powdered CLF−HPMCP dispersions with CLF/HPMCP (w/w) ratios increasing from 1:0.25 to 1:2 are shown in Figure 2. The amorphous form of CLF could be effectively maintained for the dispersion with a 0.75:1 ratio of HPMCP to CLF. In comparison to the limited amorphous drug loading reported for CLF dispersions prepared with neutral polymeric carriers,13 the ASD of CLF−HPMCP was shown to have a superior drug loading capacity (∼60%) indicating that HPMCP is an effective crystallization inhibitor for amorphous CLF. Hence, formation of strong intermolecular interactions is expected between CLF and HPMCP. To better investigate the specific drug−polymer interaction, understanding the chemical features of free drug and polymer molecules is a reasonable starting point. Natural population analysis (NPA) was applied herein to scrutinize the atomic charges of CLF (Figure 1C, details of charges are attached in Tables S2−S4) as a means to identify potential interaction sites of drug molecules.47 In Figure 1, panel C, the atomic charge of Nα (−0.535e), which is part of the imine group, was shown to have the most negative value throughout the CLF molecule, which implied a potential for serving as a strong proton acceptor. On the other hand, Hβ, located at the secondary amine group, stood out as the most positively charged atom (+0.425e), which indicated that the NH group is capable of being a proton donor. In addition, on the basis of the geometrical characteristics of hydrogen bonds, the close atomic range between the Hβ and Nα (1.976 Å) enables the formation of a partial intramolecular hydrogen bond.48,49 The existence of such an intramolecular interaction can impair the intermolecular interaction between Hβ and other acceptors. Hence, polymeric carriers with chemical structures containing only acceptor groups are expected to have limited inhibitory effects on the crystallization of CLF. This expectation is in satisfactory agreement with previous research: lacking of proton donor groups to interact with Nα, PVP was shown as a poor polymeric inhibitor to disrupting the self-assembly of CLF.50 According to the chemical structure of HPMCP shown in Figure 1, panel B, one substituent of particular interest is the phthalyl group, which is expected to be a key functional group in bonding with CLF. To be specific, the carboxylic acid of the phthalyl can not only be a strong hydrogen bond donor, but D


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Figure 3. Solid-state UV−vis spectra of CLF and HPMCP dispersions with different CLF/HPMCP weight ratios (A); first principal component score values calculated from UV−vis spectra in the wavelength region of 380−600 nm versus the weight fraction of HPMCP/CLF (w/w) (B).

Figure 4. IR spectra of CLF−HPMCP with different CLF/HPMC weight ratios in the spectral region from 4000−2200 cm−1 (A) and region of 1850−1650 cm−1 (B).

sharpest changes of the PC1 score value were observed for the intermediate compositions (CLF/HPMCP = 1:0.75 or 1) of this titration curve. Similar quantitative results of correlating the spectral variables and polymer content of dispersions can be found from the mid-IR and ssNMR studies (vide inf ra). IR Spectroscopy. IR spectra of dispersions were evaluated herein to delineate how the drug−polymer interaction resulted in changes of vibrational modes for the involved chemical moieties of CLF or HPMCP. It is noteworthy that neat amorphous CLF cannot be prepared by spin coating method because CLF is a fast crystallizer. Hence, the spectrum of pure CLF in crystalline form was used herein for comparison. According to Figure 4, panel A, a clear new peak (peak A) appears at 3310 cm−1 in the IR spectra of the CLF−HPMCP dispersions. This new peak corresponds to the Nα−H+ stretching of the protonated imine group. Interestingly, peak A was absent for dispersions with ratio of CLF/HPMCP less than 1:0.5 (w/w), which suggested that the low concentration of carboxylic acid groups in the phthalyl substituent can only protonate limited amount of the imine group. As the

concentration of the HPMCP in dispersions increased, the intensity of peak A was enhanced accordingly. This finding is in a good agreement with the UV−vis spectra discussed previously. HPMCP alone has a fairly broad peak centered at 1724 cm−1 (peak B) assigned to the stretching of the carboxylic acid CO group. The carboxylic acid from the phthalyl substituents can be converted to carboxylate group by forming ionic interaction with CLF. This interaction is supported by the appearance of peak at 1540 cm−1 (Figure 5, peak D) and 1395 cm−1 (Figure 5, peak F), which can be assigned to the antisymmetric and symmetric stretching of the carboxylate group. A hypsochromic shift of Peak B from 1724 to 1733 cm−1 in the IR spectra of dispersions was also noted (Figure 4B), and this may be due to some accompanying changes in the hydrogen bond interactions of CO groups. More evidence of the existence of acid base interactions between CLF and HPMCP can be found from the changes of spectra features in the region of 1650−1350 cm−1 (Figure 5). Specifically, peak C located at 1626 cm −1 corresponds to the stretching of CNα from the imine group. In the presence of HPMCP, peak C undergoes a E


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(in green) in CLF from all other peaks, which provides good probes to detect possible perturbation of local structures. The spectral comparison of CLF−HPMCP dispersions at various API/polymer weigh ratios is exhibited in Figure 8, panel A. Spectral features of CLF peaks in terms of line width and resonance position largely match with the melt-quenched API, which confirm the amorphous state. The only exception is the 13 C spectrum of the dispersion sample at the CLF/HPMCP ratio of 1:0.25, which contains a large amount of sharp peaks from crystalline content. This confirms the PXRD finding in Figure 2. Interestingly, chemical shift changes of −CO and isopropyl-C peaks, respectively, in HPMCP and CLF, are observed in Figure 8, panels A and B, which suggest the molecular interaction between these two groups. Specifically, as summarized in Table S1, 13C chemical shift of isopropyl-C of pure CLF in crystalline and amorphous forms shows a peak at 49.4 ppm. In dispersion samples, this peak shifts to upfield positions, for example, 47.0 ppm at the CLF/HPMCP ratio of 1:9. The chemical shift difference of isopropyl-C between pure CLF and the ASD is correlated with the computational results in Table 1 for determining a model of the CLF−HPMCP complex, which will be discussed more in the next section. Moreover, the 13C resonance of carboxylic acid CO in pure polymer is at 169.5 ppm and shifts to a new position at 174.2 ppm in CLF−HPMCP dispersions (Figure 8B), assigned to the carboxylate bound to CLF. The intensity and area of this new component grow at a higher drug loading. For this drug-loading dependent peak change, PCA in the spectral range of 161−185 ppm shows the sharpest change of the score value at the CLF/ HPMCP ratio equal to 1 (Figure 8C), in good agreement with the findings of UV−vis and IR spectroscopy. Under ultrafast MAS spinning, we have acquired 1D 1H spectra of amorphous CLF, HPMCP, and CLF−HPMCP ASD at 1:1 ratio, as shown in Figure S2. To extract structural information from correlation spectroscopy, we extend the 1H detection to a 2D mode. 1H double quantum (DQ) correlation experiment utilizing back-to-back (BABA) excitation and reconversion pulse scheme has shown the capability of detecting close contacts of up to 5 Å in pharmaceutical solids.30,32,36,62 The 2D 1H−1H spectra of pure CLF and HPMCP are included in Figure 9, panels A and B, respectively, which show the correlation between aliphatic and aromatic protons. Hypothetically, the formation of CLF−HPMCP ASD involves proton transfer from −COOH of polymer to Nα of CLF. This formation of a new Nα and Hα contact, if it exists, will impact the local electronic configuration of Nβ−Hβ. Therefore, it would be of particular interest to pay attention to peaks of protons attached to both Nα and Nβ (exist only if the proton transfer happens). The proton chemical shift of Nβ− Hβ in pure CLF has been experimentally measured to be 8.6 ppm in chloroform in our previous study, which is presumably overlapped with the aromatic protons in Figure 9, panel A. On the basis of this assumption, the possible intramolecular correlations between Hβ and other protons within the same CLF molecule will be underneath the aliphatic-aromatic cross peaks. HPMCP has no N−H groups and thus no amine proton peak in Figure 9, panel B. Very interestingly, a pair of new cross peaks at 11.5 and 10.0 ppm, respectively, appears in the spectrum of the HPMCP ASD (50% CLF by weight) in Figure 9, panel C, with equal peak intensity as shown in the 1D slice in red. These relatively large chemical shifts are very likely to be assigned to protons adjacent to a nitrogen atom in the current molecular systems. Considering both the fact that no N−H

Figure 5. IR spectra of CLF−HPMCP with different CLF/HPMC weight ratios in the spectral region of 1650−1350 cm−1.

bathochromic shift to 1619 cm−1, which indicates that protonation of Nα leads to changes in the vibrational properties of the imine group. This observation is consistent with a previous report of a similar red-shift of imine peak in the IR spectra of CLF salts prepared with low-molecular weight counterions such as maleic acid or isonicotinic acid.61 Finally, the appearance of an intense new peak at 1481 cm−1 (peak E) is assigned to Nα H+ deformation, which further supports the protonation of Nα. Spectral regions containing peaks A−F were subjected to PCA to further quantitatively study the relationship between HPMCP content and acid−base interactions. Plots of PC1 scores against the HPMCP/CLF weight ratio for each peak are shown in Figure 6, panels A−F. Each plot shows good agreement with the score plots obtained from the UV−vis spectra. For the HPMCP/CLF ratio in the range of 0.75:1, the steepest changes of the PC1 score value were noted, which indicate that CLF consists of a mixture of the ionized and neutral states at these polymer concentrations. A detailed calculation of the molar ratio of drug and polymer and how this determines the optimized polymer concentration will be further discussed in detail. Solid-State NMR Spectroscopy. Intermolecular geometry between API and polymer carrier has been successfully detected by dipolar based ssNMR experiments utilizing cross-polarization, spin diffusion effect, and multiquantum correlations.26,27 To further obtain site-specific information at a molecular level, we have utilized ssNMR to elucidate the structural basis of the interactions between CLF and HPMCP. Figure 7 shows the 13C CP-MAS spectra of the HPMCP and melt-quenched and as-received CLF. The relatively broad peaks, that is, 13C peak width at full width at half-maximum (fwhm) of 4.1−7.1 ppm and 2.8−3.8 ppm, respectively, for polymer and melt-quenched API, indicate the amorphous nature of the two samples. In comparison, the crystalline CLF has a relatively sharp 13C peak of ∼1.0 ppm. It is useful to note the resolved −CO peak (in red) of HPMCP and isopropyl-C F


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Figure 6. Plots of the score value of the first principal component, calculated from IR spectra in the regions containing peaks A−F versus the weight fraction of HPMCP/CLF (w/w).

Computational Analysis. The aforementioned experimental investigations provide valuable spectroscopic evidence for understanding the molecular interactions with CLF−HPMCP ASDs. Computational modeling is applied herein to better interpret these experimental findings to elucidate the interaction mechanism and depict critical structure elements of CLF−HPMCP complex. Since the carboxylic acid of HPMCP is the key chemical moiety to bond with CLF, the HPMCP structure was simplified as acetic acid in the computational modeling for ease of calculation. Two possible structures of CLF and carboxylic acid complex (complex I and complex II) with optimized geometrical positions and different binding motifs were proposed herein according to a previously published report.13,61 Briefly, ionic

containing compound has been introduced in forming the ASD and characteristic chemical shifts, these two new resonances can be assigned to the existing Nβ−Hβ and the newly formed Nα− Hα. As shown in Table 2, computational data in the next section show a peak shift to downfield for Hβ when bound to polymer, which results in the resolved peak in the spectrum of ASD. It is important to observe the cross peaks between Hα− Hβ in the quantum-single quantum (DQ-SQ) BABA spectrum of the CLF−HPMCP complex. A correlation in a relatively short DQ excitation time should result from strongly dipolar coupled spins. This has experimentally confirmed that the two protons, that is, Hα and Hβ, have close distance in space. Understanding the Mechanism of CLF−HPMCP Interaction from Correlating ssNMR Findings and G


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Table 1. Calculated NMR Chemical Shifts (ppm) and Experimental Chemical Shifts (ppm) for Isopropyl-C (−CH(CH3)2) in Pure CLF and CLF−HPMCP Complex (1:1, w/w)a experimental chemical shifts 13

C

isopropyl-C a

pure CLF 49.4

calculated chemical shifts

CLF+HPMCP

pure CLF

complex I

complex II

47.5

53.2

51.1

55.32

Refer to Figure 10 for schematic structures of complexes I and II.

Figure 7. 13C CP-MAS NMR spectra of HPMCP (top), as-received crystalline CLF (middle), and amorphous CLF prepared by melt quenching (bottom).

Figure 8. 13C CP-MAS NMR spectra of CLF−HPMCP dispersions with different API/polymer weight ratios (A) and the enlarged spectral region from 157−183 ppm (B); plots of the score value of first principal component in PCA for peaks in the carbonyl region (161− 185 ppm) (C).

Figure 9. 2D 1H−1H DQ-SQ BABA ssNMR spectra of a morphous CLF (A), HPMCP (B), and CLF−HPMCP ASD with 50% drug loading (C). The 1D slice at 21.5 ppm (indirect dimension and DQ frequency) is shown in red in panel C. 1D projections are shown along with all 2Ds. All spectra are acquired at a MAS frequency of 60 kHz.

interaction was formed in complex I (Figure 10A, Table S3) between the protonated imine group of CLF (NαH+) and the carboxylate group. In addition, NαH+ and the secondary amide group (NβH) formed a bifurcated hydrogen bond with the COO− group to further stabilize complex I. On the other hand, the bonding motif of complex II (Figure 10B, Table S4) was proposed as forming a hydrogen bond dimer between CLF and

HPMCP without proton transfer. The atomic distance between Hα and Hβ is 1.702 and 2.176 Å in complex I and II, respectively; hence, both are within the detection range of the 1 H DQ BABA experiment. Simulated NMR chemical shifts of each complex were calculated by methods described in the Experimental Section H


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ppm, while this peak was shielded to 47.5 ppm for 50% drug loading CLF−HPMCP ASD. For the simulated NMR spectrum, we observed that this peak upfield shifted from 53.2 to 51.1 ppm (Table 1) showing a satisfactory concurrence with the experimental result. In contrast, the peak of isopropyl moiety shows a downfield shift for complex II (Table 1), which exhibits an obvious discrepancy with experimental chemical shift. Moreover, for the 50% drug loading CLF−HPMCP dispersion, the chemical shifts of Hα and Hβ are experimentally reported as 11.5 and 10.0 ppm, respectively, in 1H NMR spectra giving a difference of 1.5 ppm. On the other hand, the simulated chemical shifts of Hα and Hβ for complex I are calculated to be 15.2 and 13.8 ppm (Table 2), while the calculated chemical shifts of Hα and Hβ become 13.7 and 9.3 ppm and apply the complex II as a model structure (Table 2). These calculated results give a chemical shift difference of 1.4 and 4.4 ppm for complex I and II, respectively. The good agreement between the experimental and computational results suggests that complex I is a better model to illustrate interactions existing in the CLF−HPMCP ASD system. Thus, these simulations can be treated as additional evidence to further support the presence of an acid−base interaction in the CLF−HPMCP ASD system and indicate that the possible molecular interaction pattern between CLF and HPMCP should be very similar to the bonding motif of complex I.

Table 2. Calculated NMR Chemical Shifts (ppm) and Experimental Chemical Shifts (ppm) for Hα and Hβ in CLF− HPMCP Complex (1:1, w/w)a experimental chemical shifts

calculated chemical shifts

H

CLFb

CLF+HPMCP ASD

complex I

complex II

Hα Hβ Δ(Hα−Hβ)

N/Ac 8.6 N/A

11.5 10.0 1.5

15.2 13.8 1.4

13.7 9.3 4.4

1

a

Chemical shift difference between the two protons is also calculated. Refer to Figure 10 for schematic structures of complexes I and II. bThe experimental chemical shift is taken from solution NMR measurement of pure CLF dissolved in chloroform.13 cN/A, not available.

(summarized in Tables S2−S4). Interestingly, the chemical shifts of the simulated NMR spectrum for complex I have a satisfactory agreement with the experimental NMR spectrum of the CLF−HPMCP dispersion. To be specific, there is a particular interest in the changes of chemical shifts of the isopropyl group in 13C CP-MAS spectra due to its direct connection to the imine group (interaction center) and lack of spectral interference from the HPMCP. According to the experimental ssNMR results, the chemical shift of the isopropyl group in 13C ssNMR spectrum of pure CLF was located at 49.4

Figure 10. Models of CLF and carboxylic acid complex I (A) and II (B) for quantum chemistry calculation; molecular mechanism of the solid-state CLF−HPMCP reaction proposed based on experimental and computational results (C). I


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scientists to design innovative formulations of amorphous solid dispersion with improved solid-state performance.

Hence, a possible binding mechanism between CLF and HPMCP with a detailed molecular structure is proposed herein (Figure 10C): Nα on the imine group of CLF is protonated by the carboxylic acid group on the phthalyl from HPMCP. The intramolecular hydrogen bond formed between Nα and the secondary amide group is cleaved to make NβH as active hydrogen bond donor. NαH+ and NβH subsequently likely form a bifurcated hydrogen bond to further enforce the binding strength between CLF and HPMCP in ASDs. To further optimize the HPMCP concentration in the ASD system, the molar ratios between the CLF and key substituents of HPMCP (phthalyl group) were calculated on the basis of the chemical reaction discussed above (Figure 10C). According to the certificate of analysis of the HPMCP HP-55 (provided by Shin-Etsu Chemical Co., Ltd.), the weight percentage of the phthalyl group is around 33%. Hence, a 1:1 molar ratio between CLF and phthalyl group is achieved when the weight ratio of CLF to HPMCP is in the approximate range of 1:0.75 to 1:1 (w/w). This molar ratio of CLF to phthalyl group be can correlated with the changes observed in the various spectra processed by multivariate analysis. To be specific, according to the plots of PC1 score value against HPMCP/CLF (w/w) ratio (Figure 3B, Figure 6A−F, Figure 8C), the sharpest PC1 score value changes were observed for dispersions with molar ratio of CLF/phthalyl is 1:1, which suggests that this is the composition where CLF is undergoing a substantial change from the neutral to the protonated state. Hence, in this case, an optimized CLF−HPMCP solid dispersion with sufficient drug−polymer interaction and superior amorphous drug loading can be achieved at a 1:1 molar ratio between CLF and phthalyl group. It is also noteworthy that only half of the CLF present is protonated by the method applied in this study at this specific CLF/phthalyl molar ratio due to the limited proton transfer ability of the nonpolar solvent used in preparing the ASDs.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.6b00740. Optimized structures, natural population analysis, and simulated NMR chemical shifts of CLF, complex I, and complex II; picture of pure CLF in crystalline form; picture of 50% drug loading CLF−HPMCP amorphous solid dispersions; 1D 1H spectra of amorphous CLF, HPMCP, and ASD of CLF−HPMCP (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank Drs.Wei Xu, Brandye Smith-Goettler, Dirk Stueber, and Fengyuan Yang at Merck Research Laboratories (MRLs) and Dr. Huaping Mo from Purdue NMR center for helpful scientific discussions. Dr. Jiannan Lu from Shin-Etsu Chemical Co., Ltd. (Totowa, NJ) is acknowledged for providing the certificate of analysis of HPMCP HP-55. In particular, authors would like to thank Dr. Thomas Williamson (MRLs) for his support with Merck NMR replacement plan.

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REFERENCES

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CONCLUSION This study serves to illustrate the utility of various solid state spectroscopic methods, alone and in combination with multivariate analysis, to evaluate the interaction pattern in ASDs from a molecular perspective, thereby reducing the reliance on time-consuming empirical polymer screening. Ionic interactions are shown to be the dominant forces present in ASD systems of CLF and HPMCP. Protonation of the imine group on the riminophenazine core results in changes of electronic properties of the chromophore, which leads to an obvious color changing phenomenon and a corresponding bathochromic peak shift in UV−vis spectrum. Spectral evidence of protonated imine and ionization of the carboxylic acid group from HPMCP can also be found from IR and 13C NMR spectra, which further confirm the formation of ionic interaction between CLF and the phthalyl group of HPMCP. Moreover, the 2D double quantum NMR spectrum of CLF− HPMCP ASD provides important structural clues for proton transfer between CLF and HPMCP. This serves as one successful example of utilizing the 2D double quantum NMR spectrum with ultrafast MAS technique (VMAS = 60 kHz) to explore drug−polymer interactions in ASDs. By combining computational chemistry with the NMR spectroscopy, molecular details of the CLF−HPMCP interaction and a possible bonding motif are delineated. We also demonstrated that PCA can be utilized to process spectra to further optimize the drug/polymer ratio based on the spectral changes. The interesting findings of this research should be helpful for J


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