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Jun 12, 2015 - ASDs of ketoconazole (KTZ), a weakly basic drug, with each of poly(acrylic acid) (PAA), poly(2-hydroxyethyl methacrylate) (PHEMA), and ...
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Role of the Strength of Drug−Polymer Interactions on the Molecular Mobility and Crystallization Inhibition in Ketoconazole Solid Dispersions Pinal Mistry,† Sarat Mohapatra,† Tata Gopinath,‡ Frederick G. Vogt,§ and Raj Suryanarayanan*,† †

Department of Pharmaceutics and ‡Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, United States § Morgan, Lewis, and Bockius LLP, Philadelphia, Pennsylvania 19103, United States S Supporting Information *

ABSTRACT: The effects of specific drug−polymer interactions (ionic or hydrogen-bonding) on the molecular mobility of model amorphous solid dispersions (ASDs) were investigated. ASDs of ketoconazole (KTZ), a weakly basic drug, with each of poly(acrylic acid) (PAA), poly(2hydroxyethyl methacrylate) (PHEMA), and polyvinylpyrrolidone (PVP) were prepared. Drug−polymer interactions in the ASDs were evaluated by infrared and solid-state NMR, the molecular mobility quantified by dielectric spectroscopy, and crystallization onset monitored by differential scanning calorimetry (DSC) and variable temperature X-ray diffractometry (VTXRD). KTZ likely exhibited ionic interactions with PAA, hydrogen-bonding with PHEMA, and weaker dipole−dipole interactions with PVP. On the basis of dielectric spectroscopy, the α-relaxation times of the ASDs followed the order: PAA > PHEMA > PVP. In addition, the presence of ionic interactions also translated to a dramatic and disproportionate decrease in mobility as a function of polymer concentration. On the basis of both DSC and VTXRD, an increase in strength of interaction translated to higher crystallization onset temperature and a decrease in extent of crystallization. Stronger drug−polymer interactions, by reducing the molecular mobility, can potentially delay the crystallization onset temperature as well as crystallization extent. KEYWORDS: ketoconazole, amorphous solid dispersions, ionic interaction, hydrogen bonding, molecular mobility, crystallization, dielectric spectroscopy, infrared spectroscopy, solid-state nuclear magnetic resonance

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INTRODUCTION Amorphous solid dispersions (ASDs) are molecular mixtures of drug and polymer that can potentially enhance the oral bioavailability of BCS Class II and IV drugs.1 However, retention of the drug in the amorphous state can be a challenge and will depend on the type and concentration of the polymer used. For example, Bhardwaj et al. compared the crystallization propensity of an itraconazole ASD prepared with hypromellose acetate succinate (HPMCAS) and polyvinylpyrrolidone (PVP). HPMCAS was much more effective in inhibiting drug crystallization than PVP.2 Interestingly, the trend was opposite in a nifedipine ASD, where PVP was more effective than HPMCAS.3 Clearly, there is no single polymer that can effectively stabilize all amorphous drugs. One approach to minimize the risk of drug crystallization is to use a high polymer concentration. From a formulation perspective, this is neither a desirable nor an elegant approach. This is also not practically feasible in the case of high-dose drugs. Thus, there is a need for a polymer selection tool that will enable the formulation of stable ASDs at minimal polymer concentrations. Currently, polymer selection is largely based on trial and error since there is only a limited basis for rational polymer © 2015 American Chemical Society

selection. Polymers with high glass transition temperatures (Tg) have the potential to stabilize drugs through their antiplasticization effect. For example, Khougaz et al. formulated a developmental compound as an ASD with five polymers and compared their stabilizing effects.4 The crystallization inhibition was a function of the polymer Tg, and the effect was attributed to the increase in the overall Tg of the ASD brought about by the polymer. However, in several instances, it has been demonstrated that Tg is not a reliable predictor of the physical stability of ASDs. For example, poly(acrylic acid) (PAA) was a better crystallization inhibitor than PVP in acetaminophen ASDs, though the Tg values were virtually identical.5 An alternative polymer selection strategy is to choose a polymer that specifically interacts with the drug. This is based on the finding that drug−polymer hydrogen bonding (H-bonding) can enhance crystallization inhibition.6−8 The influence of drug− polymer H-bonding interactions on molecular mobility and the Received: Revised: Accepted: Published: 3339

April 29, 2015 June 10, 2015 June 12, 2015 June 12, 2015 DOI: 10.1021/acs.molpharmaceut.5b00333 Mol. Pharmaceutics 2015, 12, 3339−3350

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Molecular Pharmaceutics physical stability in ASDs of nifedipine with each PVP, HPMCAS, and PAA was compared.3 The strength of drug− polymer H-bonding, the α-relaxation time, and crystallization inhibition were rank ordered as PVP > HPMCAS > PAA. Further enhancement in stability may be achieved if there is an ionic interaction between drug and polymer since such interactions are stronger than H-bonds. Ionic interactions between drug and excipient enhanced the physical stability of amorphous drugs. For example, milling-induced acid−base reactions between drugs and inorganic silicates resulted in the formation of physically stable amorphous drugs.9−12 The reaction of magnesium aluminosilicate with each indomethacin, naproxen, and ketoprofen resulted in stabilization of the drug in the amorphous state. In ASDs, crystallization inhibition has been attributed to ionic interactions between drug and polymer.13−16 For example, ionic interactions between indomethacin and dimethylaminoethyl methacrylate copolymer prevented drug dimer formation and resulted in a stable ASD.17 Although the enhanced physical stability was explained by drug−polymer ionic interactions, the specific mechanism governing crystallization inhibition was not elucidated. From a mechanistic point of view, reduced molecular mobility is one possible consequence of ionic interactions. Molecular mobility is believed to play an important role in the physical stability of ASDs.5,18−20 We hypothesize that the strength of interaction between drug and polymer in solid dispersions governs the degree of reduction in molecular mobility and consequently the delay in crystallization. We prepared ASDs of ketoconazole (KTZ, a weakly basic drug) with each PAA, poly(2-hydroxyethyl methacrylate) (PHEMA), and PVP (Figure 1). These polymers differed in their abilities to specifically interact with KTZ. We investigated the drug− polymer interactions in the ASDs using infrared (IR) and solidstate NMR spectroscopy. The α-relaxation time, a measure of molecular mobility, was determined in the ASDs at different polymer concentrations by dielectric spectroscopy. The crystallization onset was monitored by differential scanning calorimetry (DSC) and variable temperature X-ray diffractometry (VTXRD). Our overall objectives were to (i) study the influence of the strength of drug−polymer interaction on the molecular mobility of the system, and the consequent effect of mobility on drug crystallization from the ASD, and (ii) explore the utility of this approach for rational polymer selection.

Figure 1. (a) Structures of KTZ, PAA, PHEMA, and PVP. (b) Species proposed to be present in the KTZ-PAA ASD, showing an ionic interaction between the N3 nitrogen in the imidazole ring of KTZ and the carboxylic acid in PAA. The proposed interactions in the KTZPHEMA ASD include two H-bonding interactions: (i) between the N3 nitrogen of the imidazole ring of KTZ and the −OH group of PHEMA, and (ii) between the CO group of KTZ and the −OH group of PHEMA.

KTZ and PVP, which makes PVP an excellent “control” for comparison with other polymers.26,27 KTZ was a generous gift from Laborate Pharmaceuticals (Haryana, India). PAA (Mw ≈ 1800) and poly(acrylic acid sodium salt) (Mw ≈ 5100) were purchased from Sigma-Aldrich (Missouri, USA), while PHEMA (Mw ≈ 3700) was commercially obtained from Polymer Source (Quebec, Canada). PVP-K12 (Mw ≈ 2000−3000) was obtained from BASF (New Jersey, USA). All the polymers were used after drying at 110 °C for 1 h. All the solvents and other chemicals were of analytical grade. Preparation of Amorphous Systems. Amorphous KTZ. Crystalline KTZ was heated to 160 °C, held for 1 min, and cooled rapidly in liquid nitrogen. The quenched materials were then gently ground using a mortar and pestle to obtain a freeflowing powder and stored at −20 °C in desiccators containing anhydrous calcium sulfate until further use. All the sample preparation and subsequent handling were done in a glovebox at RH < 5% (room temperature). Preparation of ASDs. ASDs of KTZ, with polymer concentration ranging between 4 and 12% w/w, were prepared by solvent evaporation followed by melt-quenching. The drug and polymer were dissolved in methanol, and the solvent was evaporated (IKA-HB10 digital system rotary evaporator, Werke

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EXPERIMENTAL SECTION Materials. The selection of model compounds (Figure 1) was based on several attributes. The model drug molecule KTZ is a weakly basic drug and is structurally similar to itraconazole. The molecular mobility and crystallization kinetics of itraconazole have been studied by our group.21 There are no reported polymorphic forms of KTZ, although its salt and cocrystal forms are reported.22 It can be readily rendered amorphous by melt quenching, and it is chemically stable at least up to 10 °C above its melting point.23,24 KTZ has been reported to interact ionically with oxalic acid, an aliphatic acid with two carboxylic acid groups.22 PAA has a carboxylic acid group in monomer unit that can serve as a proton donor. PHEMA is a biocompatible polymer capable of H-bonding interactions through its hydroxyl group. It has exhibited Hbonding interactions with imidazole ring of poly(1-vinylimidazole).25 PVP is widely used in model ASDs. KTZ-PVP ASDs have been reported to lack specific interactions between 3340

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Molecular Pharmaceutics GmbH and Co., Staufen, Germany) at 50 °C under reduced pressure. The powder was further dried at 50 °C under reduced pressure for 45 min to remove residual solvent. It was then melt-quenched using the same procedure as described for preparation of amorphous KTZ. Karl Fischer Titrimetry. The water content in the amorphous systems was determined using coulometric Karl Fischer titration (C20 Coulometeric KF titrator, Mettler Toledo, Ohio, USA). These titrations were carried out using approximately 120−140 mg of sample. Differential Scanning Calorimetry (DSC). A differential scanning calorimeter (TA Instruments Q2000, Delaware, USA) equipped with a refrigerated cooling accessory was used. The instrument was calibrated with indium. Approximately 5−10 mg of sample was hermetically sealed in an aluminum pan inside a glovebox. All measurements were performed at a rate of 10 °C/min under nitrogen purge (50 mL/min). The Tg value was determined at the midpoint of the transition, and the enthalpy of crystallization (ΔHc) was normalized for KTZ content. For ΔCp measurements, the instrument was operated in modulation mode and calibrated using sapphire. The temperature modulation was ±0.75 °C every 100 s with an underlying heating rate of 2 °C/min. Fourier Transform Infrared Spectroscopy (IR). IR spectra were obtained at room temperature in the transmission mode using KBr pellet method in Bruker Vertex 70 spectrometer (Massachusetts, USA). KBr pellets (sample: KBr weight ratio of approximately 1:100) were compressed into 13 mm die at high pressure (5 tons). At a resolution of 4 cm−1, 128 scans were obtained across the spectral range of 4000−400 cm−1. A background spectrum (KBr pellet without the sample) was collected under the same experimental conditions and was subtracted from each sample spectrum. A baseline correction was applied to all the samples using the rubberband correction method (OPUS software, Bruker Optics, Wisconsin, USA). Solid-State NMR Spectroscopy. Experimental Methods. Solid-state NMR experiments were run on 700 MHz Agilent or Bruker spectrometers at −10 °C and 10 kHz magic angle spinning (MAS) under similar experimental conditions. For 13C and 15N spectra, Hartmann−Hann cross-polarization (CP) was used with contact times of 1 and 2 ms, respectively. The spectra were acquired with 3 s recycle delay and 20 ms acquisition time under 1H SPINAL decoupling with 100 kHz RF amplitude. During CP, 1H, 13C, and 15N RF amplitudes were respectively set to 50, 40, and 40 kHz. 13C spectra were acquired with 1000 scans, and 15N spectra were acquired with a total number of 20 000−50 000 scans depending on the sample sensitivity. The spectra were processed using nmrpipe software. 28 An exponential line broadening of 100 and 200 Hz was used for 13 C and 15N spectra before Fourier transformation. The 13C spectra were externally referenced with respect to the α-glycine 13 C resonance at 45 ppm, and 15N spectra were indirectly referenced to ammonia by using the relative gyromagnetic ratio of 13C and 15N.29 Computational Methods. NMR chemical shielding calculations were performed to support spectral interpretations using a gas-phase model system, which was designed to be similar to the effects expected in the KTZ-PAA ASD and which consisted of an H-bonded dimer of isobutyric acid and N-methylimidazole. Density functional theory (DFT) chemical shielding calculations were performed using the Gaussian 09 software package.30 The B3LYP density functional, 6-311++G(2d,p)

Gaussian basis set, and the gauge-independent atomic orbital (GIAO) method were used to perform the calculations.31,32 Results and additional details are given in the Supporting Information. Dielectric Spectroscopy. A dielectric spectrometer (Novocontrol Alpha-AK high performance frequency analyzer, Novocontrol Technologies, Germany) equipped with a temperature controller (Novocool Cryosystem) was used to perform isothermal dielectric measurements at temperatures between 40 and 110 °C in steps of 2.5 °C, in the frequency range of 10−2−106 Hz. The amorphous sample in powder form was placed between two gold-plated copper electrodes (20 mm diameter), separated by a polytetrafluoroethylene (PTFE) spacer (1 mm thickness, 59.69 mm2 area, and 1.036 pF capacitance). A PTFE spacer was used to confine the sample between the electrodes. The validity of the relaxation time measurements obtained using powder samples has been previously documented by our group.33 All dielectric measurements were corrected for stray capacitance, spacer capacitance, and edge compensation. To determine the average α-relaxation time (τ), the Havriliak−Negami (HN) model (eq 1) was used to fit the dielectric data:34 ε*(ω) = ε∞ +

Δε (1 + (iωτHN)βHN )γHN

(1)

In this equation, ε*(ω) is the complex dielectric permittivity consisting of real (ε′) and imaginary (ε″) components that is obtained from the dielectric data, ω is the angular frequency, and Δε is the dielectric strength given by Δε = εs − ε∞, where εs gives the low frequency limit (ω → 0) of ε′(ω), and ε∞ is the high frequency limit (ω → ∞) of ε′(ω). The shape parameters account for the symmetric (βHN) and asymmetric (γHN) peak broadening with 0 < βHN (or γHN) < 1. At higher temperatures, the contribution of dc conductivity was observed on the low frequency side of the dielectric spectra. This contribution of conductivity was taken into account by adding the conductivity component, σdc/iωεo to the HN equation, where σdc is the dc conductivity, and εo is the vacuum permittivity. Variable Temperature X-ray Powder Diffraction (VTXRD). ASDs with 4% w/w polymer concentration were evaluated using an X-ray diffractometer (D8 ADVANCE, Bruker AXS, Wisconsin, USA) equipped with a variabletemperature stage (TTK 450; Anton Paar, Graz-Straßgang, Austria) and a Si strip one-dimensional detector (LynxEye; Bruker AXS, Wisconsin, USA). The measurements were performed in 5 °C increments from 70 °C up to 150 °C. Cu Kα radiation (1.54 Å, 40 kV X 40 mA) was used, and data were collected in the range of 10−30° 2θ with a step size of 0.05° 2θ and a 0.5 s dwell time. The heating rate was 12 °C/min, and the sample was maintained under isothermal conditions during each XRD experiment (∼4 min).

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RESULTS AND DISCUSSION Baseline Characterization. The amorphous KTZ prepared by melt quenching as well as all the KTZ ASDs were found to be amorphous by X-ray diffractometry (data not shown). The water content in all the ASDs, as determined by Karl Fischer titrimetry, was 20% w/w in indomethacin. In our studies, even at modest polymer concentrations (∼8−12% w/w), the DSC technique is not discriminating, and the polymers exhibit nearly identical (complete) crystallization inhibition. The ΔCp at Tg of amorphous KTZ was 0.38 J/g °C, in agreement with the reported value of 0.46 J/g °C.38 The ΔCp values of the ASDs were unaffected by the type and concentration of polymer (Figure S1, Supporting Information). The Tg values as a function of polymer concentration were also calculated using the Fox equation (Table 1).39 The most pronounced deviation between calculated and experimental Tg values was observed in the PAA system. A strong drug− polymer interaction is one possible explanation for this observation. The deviation is not very pronounced since the polymer concentration was low. However, when we determined the Tg values of these systems at higher polymer concentrations (up to 40% w/w polymer), the deviation was readily discernible in PAA systems (Figure S2, Supporting Information). Thus, if drug−polymer interactions lead to deviations from the Fox equations, this may not be readily evident when the polymer concentration is low. Therefore, in ASDs with high drug loading, the Tg value cannot be a reliable indicator of such interactions. Spectroscopic Investigation of Drug−Polymer Interactions. Infrared Spectroscopy. The IR spectrum of KTZPAA ASD revealed a peak at 1605 cm−1 and a shoulder at 2500

Figure 2. Representative DSC curves of amorphous KTZ (green) and ASDs (4% w/w polymer) of KTZ with each PVP (red), PHEMA (blue), and PAA (black). Inset shows crystallization followed by melting in PAA ASD.

observed Tg value was in excellent agreement with literature reports of ∼45 °C.26,35 In the PAA ASDs, the presence of polymer, in a concentration dependent manner, resulted in an increase in the Tg (Table 1). In the PHEMA and PVP ASDs, the progressive polymer addition first caused a small decrease and then an increase in Tg as compared to that with KTZ alone. The enthalpy of crystallization, ΔHc, an indicator of extent of KTZ crystallization, was affected by the addition of polymer. PAA appeared to be the most effective in inhibiting crystallization. The delay in crystallization onset was also most pronounced with PAA. We also evaluated the effect of each polymer and its concentration in greater detail. The Tg of the ASD with 4% w/ w polymer was close to that of KTZ. This is not surprising in light of the low polymer concentration.8,36 However, the inhibition in KTZ crystallization was strongly polymerdependent and can be rank ordered as PAA > PHEMA > PVP. The results are summarized in Table 1. ΔHc follows the reverse order with PAA showing the lowest enthalpy value. Table 1. Thermal Characterization of KTZ ASDs

Tg (°C) sample KTZ PAA ASD

PHEMA ASD

PVP ASD

a

polymer concentration (% w/w)

predicted

0 4 6 8 10 12 4 6 8 10 12 4 6 8 10 12

47 48 49 50 51 47 48 49 50 51 47 48 49 50 51

crystallization temperature (°C)

experimental 45.6 47.3 51.0 52.7 55.8 58.2 43.7 44.8 46.5 46.7 48.6 42.9 43.6 45.7 46.2 46.6

(0.3)a (0.3) (0.7) (0.5) (0.6) (1.1) (0.2) (0.2) (0.2) (0.3) (0.3) (0.4) (0.4) (0.9) (0.1) (0.3)

onset 108.7 (0.3) 117.2 (1.4) 121.1 (3.1)

116.6 116.7 118.2 119.3 120.8 110.2 116.1 117.9 119.7 120.4

(0.3) (0.7) (0.1) (1.0) (0.8) (0.2) (0.6) (0.3) (2.5) (0.1)

peak 123.5 138.1 140.7 NCc NC NC 133.1 136.2 136.6 137.5 140.4 125.7 131.3 135.7 138.8 137.3

ΔHc (J/g)b

(0.5) (1.1) (2.1)

77.9 (3.1) 1.8 (0.5) 0.4 (0.1)

(0.9) (0.4) (0.4) (1.1) (1.1) (0.1) (0.2) (1.0) (0.9) (0.5)

10.8 3.3 1.6 0.6 0.3 46.6 2.9 2.7 0.7 0.9

(0.6) (0.4) (0.0) (0.1) (0.1) (3.2) (0.4) (0.7) (0.2) (0.3)

Mean (SD); n ≥ 3. bThe enthalpy value has been normalized for the drug content in the ASD. cNC, no crystallization. 3342

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Figure 3. IR spectra of KTZ-PAA system showing (a) N+−H peak and (b) COO− peak in ASDs. The polymer concentrations are indicated as % by weight.

Figure 4. IR spectra of physical mixtures (a, c) and ASDs (b, d) of KTZ and PHEMA. The polymer concentrations are expressed as % w/w.

cm−1 that were absent, both in the IR spectra of the individual components and the drug−polymer physical mixture (Figure 3). The peak appearing at 1605 cm−1 is attributable to the asymmetric stretching vibrations of COO− group indicating ionization of carboxylic acid functional group of PAA in ASD. The shoulder at 2500 cm−1 in the spectrum of the KTZ-PAA ASD can be assigned to the N+−H stretching vibrations resulting from the protonation of the imidazole group of KTZ.17,40−42 Another interesting change in the spectral features can be noted in the 1700−1800 cm−1 region. PAA has been shown to self-associate through extensive H-bonding interactions, evident from its IR spectrum.43 In PAA, the CO stretching vibration

peak appears around 1709 cm−1 with a shoulder at ∼1743 cm−1, attributed to the H-bonded (intramolecular and possibly intermolecular) and free carboxyl groups, respectively. The PAA-KTZ ASD shows a change in the IR spectrum in this wavelength region, which can be explained by salt formation. Upon ionization, conversion of the carboxylic acid functional group to carboxylate anion (COO−) leads to appearance of a carboxylate ion peak at 1605 cm−1. The remaining unionized fraction of carboxylic acid appears as a peak at ∼1730 cm−1. The decrease in total absorbance intensity of this carboxylic acid peak can be explained by conversion of the carboxylic acid functional group to carboxylate anion (COO−). Similar 3343

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Figure 5. IR spectra of KTZ-PVP system showing increased intensity of CO peak of PVP in ASDs. The spectra obtained from physical mixtures and ASDs are shown in panels a and b, respectively.

Figure 6. 13C and 15N solid-state NMR spectra showing changes in the chemical shift in KTZ-PAA (A, B) and KTZ-PHEMA (C, D) amorphous systems.

interesting evidence is the appearance of a shoulder (∼1707 cm−1; Figure 4c) of the CO group of PHEMA (1728 cm−1), which is assigned to H-bonding between CO and −OH groups in PHEMA (both intra- and intermolecular). There appears to be a decrease in the “self-associated” H-bonded fraction in the ASDs (particularly evident in the 50% PHEMA ASD; Figure 4d) based on the reduction in the intensity of this shoulder. The IR spectra of the physical mixtures and ASDs of KTZPVP are shown in Figure 5. As noted previously, earlier literature reports had indicated no specific interaction between KTZ and PVP.26,27 The peaks observed in the ASDs could be ascribed to the individual components (Figure 5). Interestingly, only in the ASDs, we observed an increase in the intensity of

observations can be made in the IR spectrum of sodium salt of PAA (Figure S3, Supporting Information). In the KTZ-PHEMA ASDs, the broad O−H vibration peak of PHEMA at 3440 cm−1 is shifted to 3390 cm−1 (Figure 4b), while no such change is observed in physical mixtures (Figure 4a). Additionally, the peak at ∼1647 cm−1 attributed to the CO vibration of KTZ reveals a shoulder at ∼1625 cm−1 in the ASDs. The shoulder grows into a peak as the polymer concentration is increased (Figure 4d). Again, these changes were not observed in the KTZ-PHEMA physical mixtures (Figure 4c). The appearance of the 50 cm−1 shift in the vibrational frequency of O−H (of PHEMA) and 22 cm−1 shift in the CO groups (of KTZ) reflects their H-bonding interactions (as proposed in Figure 1b). An additional 3344

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Molecular Pharmaceutics the amide carbonyl band of PVP (1678 cm−1). This increased intensity can be attributed to dipole−dipole interactions between KTZ and PVP.35 Similar interactions with PVP have been reported in another model compound.4 Solid-State NMR Spectroscopy. Drug−polymer interactions were further evaluated using solid-state NMR spectroscopy. Figure 6 shows the 13C and 15N NMR spectra of selected KTZ−polymer ASDs, physical mixtures, and the individual components. As expected, given the absence of drug−polymer interactions in the physical mixtures, the 13C and 15N spectra of the physical mixtures are a summation of the spectra of individual components. For the resonance assigned to the carboxylate carbon of PAA, the 13C spectrum of the ASD (Figure 6A) showed a 4.8 ppm shift to higher frequency relative to the physical mixture (183.5 → 179.2 ppm). This result is consistent with the previously discussed carboxylate peak observed in the IR spectrum and further supports the conclusion that disruption of dimeric H-bonding within PAA molecules has occurred. The shielding effect observed in the 13 C spectrum is a consequence of this disruption, and thus a shift to higher frequency is expected.44 The ionization of PAA would result in weakening of polymer−polymer interactions through disruption of dimeric PAA H-bonding. The ionized carboxylate and N+−H stretching IR bands in this ASD also point toward at least partial ionization of PAA. Although 13C carbonyl resonances typically show a deshielding trend toward lower frequency upon deprotonation of a carboxylic acid group,45 this ionization effect might be partially offset by the loss of H-bonding. The spectral overlap (Figure 6A) prevents further detailed investigation of this effect. The ionization effects and the H-bonding effects on 13C shifts described above were both confirmed by the DFT-based NMR chemical shielding calculations described below. Direct insight into the nitrogen environment in KTZ, specifically for studying potential ionization of KTZ and other interactions in the KTZ ASDs, was obtained by 15N solidstate NMR. The 15N spectra of KTZ, the KTZ-PAA ASDs, and the KTZ-PAA physical mixture are compared in Figure 6, panel B. In the spectrum of the PAA (12%) ASD, two distinct resonances arising from the imidazole N3 nitrogen in KTZ were observed and are assigned to (i) “free” KTZ (∼260.3 ppm) and (ii) H-bonded KTZ (∼241.5 ppm) where the N3 nitrogen acts as the H-bond acceptor. Stronger H-bonding interactions to aromatic nitrogen acceptors, such as those associated with shorter donor−acceptor distances, generally result in more shielded resonances that shift to higher frequency, and in the case of N-methylimidazole, a ∼20 ppm shift is observed for the formation of H-bonds to the nitrogen analogous to N3 in KTZ.46 This shift is consistent with the observed shift difference of ∼18.8 ppm between the two N3 resonances in the KTZ-12% PAA spectrum. In contrast, the 15N solid-state NMR spectrum of the KTZ-30% PAA ASD shows only the KTZ species engaged in H-bonding (∼242.3 ppm), in agreement with the increased availability of carboxylic acid (donor) when the PAA concentration is high. To verify this trend and further investigate the influence of H-bond distance on 15N chemical shielding (and thus chemical shift), DFTbased NMR chemical shielding calculations were performed for a model system of isobutyric acid (representing PAA) Hbonded to N-methylimidazole (representing KTZ), as described in the Supporting Information. The system was simplified in that only the donor−acceptor distance between N3 and the carboxylic acid donor oxygen was varied; no

variation was made in H-bond angle, which was close to 180° after energy minimization. The results showed that the 15N isotropic chemical shielding increased in a nearly linear manner by approximately 15 ppm as the donor−acceptor distance decreased over a range of 1.7 Å, in agreement with the literature range (see Supporting Information).46 This supports the assignment given above for the N3 resonances in the KTZ12% PAA ASD. The results also show that the H-bond responsible for this relatively pronounced ∼18.8 ppm chemical shift change is likely to be strong and energetically favor stable ASD. Because of the observation of ionization effects by IR in the KTZ-30% PAA ASD (through the detection of an ionized carboxylate IR band and an N+−H stretching vibration), further consideration was given to the likely influence of such effects on the 15N spectrum of this ASD. Ionization of N-methylimidazole at the position analogous to the N3 position in KTZ results in a chemical shift change toward higher frequency of approximately 80 ppm.47,48 This effect was verified using DFT calculations again using the model system of isobutyric acid and N-methylimidazole. To simulate ionization, the gas-phase H-bonded dimer at its energy-optimized geometry was used as a starting point, and the proton position was manually varied so that it approached the N3 position (see Supporting Information). The results showed that the 15N isotropic chemical shielding increased in a nearly linear manner by approximately 67 ppm as ionization occurred over a proton-transfer distance range of 0.8 Å, again in agreement with the literature reports.47,48 The literature trends and calculated results thus indicate that an ionized N3 position would likely appear in the 15N spectrum at a chemical shift of about 170−180 ppm. Closer inspection of the 15N spectrum of the KTZ-30% PAA ASD in Figure 6, panel B suggests a weak shoulder on the front edge of the strong 15N signal at 165 ppm (which is assigned to the N1 position) and is therefore consistent with the presence of ionized N3 positions in this material. Since the N3 peak is weak, even if there is significant ionic interaction, it is likely to be “buried” under the N1 peak. The 15N solid-state NMR results thus provide tentative support for the IR interpretation that KTZ in the KTZ-30% PAA ASD is at least partially ionized, as drawn in Figure 1, panel b. No pronounced changes in chemical shifts were observed between the 13C spectra of KTZ-PHEMA physical mixtures and solid ASDs (Figure 6C). However, in the 15N spectrum of the KTZ-PHEMA ASD, the chemical shift of the N3 nitrogen showed a 5.8 ppm shift to higher frequency (260.3 → 254.5 ppm) relative to KTZ, which suggests the formation of shorter H-bonds between the N3 nitrogen of KTZ and the hydroxyl donor of the PHEMA polymer (Figure 6D). The decreased magnitude of the shift relative to that observed in the KTZPAA ASDs (5.8 ppm versus 18.8 ppm) suggests that the Hbonds are significantly longer or less numerous in this ASD. The DFT-based NMR chemical shielding calculations for the model system suggest that this H-bond may be approximately 0.6 Å longer (in terms of donor−acceptor distance) than in the KTZ-30% PAA ASD and thus likely to be less energetically favorable. The 13C solid-state NMR spectra of KTZ-PVP ASDs and the physical mixtures were identical.26 Therefore, we did not perform any additional solid-state NMR experiments on the KTZ-PVP ASDs. The strength of interaction varies considerably with the type of interaction between molecules. Typically, the energy of ionic 3345

DOI: 10.1021/acs.molpharmaceut.5b00333 Mol. Pharmaceutics 2015, 12, 3339−3350

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Figure 7. (a) Dielectric loss spectra of amorphous KTZ as a function of temperature. For the sake of clarity, the spectra at only select temperatures are shown. (b) Dielectric loss spectra of KTZ and ASDs of KTZ (with each PAA, PHEMA, and PVP). The polymer concentration was 8% w/w, and only the spectra obtained at 70 °C are shown. After the conductivity contribution was subtracted, the curves were normalized with respect to the maximum loss value. The solid line represents the HN model fitted to the data.

Figure 8. Temperature dependence of α-relaxation times in KTZ ASDs with (a) PAA, (b) PHEMA, and (c) PVP. The polymer concentration ranged from 4−12% w/w. (d) Temperature dependence of α-relaxation times at 8% w/w polymer concentration. A vertical line is drawn at 70 °C.

acid of PAA. In the KTZ-PHEMA system, H-bonding was evident between each N3 and CO of KTZ (acceptors) and the −OH (donor) of PHEMA.22,25 The KTZ-PVP system likely exhibited only weaker (e.g., dipole−dipole and van der Waals) interactions between the drug and PVP. Thus, on the basis of the available spectroscopic evidence, the strength of drug−polymer interactions in these amorphous systems can be rank ordered as PAA > PHEMA > PVP. Interestingly, the use of a single technique did not enable adequate characterization of the drug−polymer interactions, and by using IR and solidstate NMR spectroscopy, a more comprehensive characterization was possible.

interactions varies from 850−1700 kJ/mol, while that of Hbonding is in the range of 50−170 kJ/mol. Dipole−dipole interactions are much weaker attractive forces, on the order of 2−8 kJ/mol.49 We probed the interactions between the drug and polymers using IR and solid-state NMR spectroscopy. The KTZ-PAA system was characterized as an ionic interaction based on the transfer of protons from the carboxylic acid group of PAA to the imidazole nitrogen N3 of KTZ. The functional groups involved (imidazole nitrogen and carboxylic acid) were previously shown to interact ionically.22,50 Furthermore, the KTZ-PAA system also shows evidence of strong H-bonding between the N3 of KTZ (H-bond acceptor) and the carboxylic 3346

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Article

Molecular Pharmaceutics Type of Drug−Polymer InteractionEffect on Molecular Mobility. Dielectric measurements enabled us to obtain the average α-relaxation times, a measure of molecular mobility. The dielectric loss spectra of amorphous KTZ, at several selected temperatures, are shown in Figure 7, panel a. The plot of dielectric loss (ε″) against frequency revealed a well-resolved peak attributed to α-relaxation (also referred to as primary or structural relaxation). In the entire temperature range, the drug existed in the supercooled state, and there was a pronounced contribution of conductivity in the low frequency region of the dielectric spectra. With an increase in temperature, the dielectric loss peak progressively moved to higher frequencies, which indicates an increase in molecular mobility and, consequently, a decrease in relaxation times. At higher temperatures (readily evident at temperatures ≥ 75 °C), crystallization of amorphous KTZ caused a decrease in the dielectric strength (Δε). The presence of a polymer, even at a low concentration, caused a reduction in molecular mobility (Figure 7b). The extent of the shift in the dielectric loss peak, to a lower frequency, was specific to each polymer. While the use of PVP and PHEMA resulted in a modest reduction in mobility, the effect of PAA was very pronounced (>2 orders of magnitude increase in relaxation time). The concentration effect of each of these polymers was evaluated in detail. Effect of Polymer Concentration. The temperature dependence of the α-relaxation times at different polymer concentrations is shown in Figure 8, panels a−c. As expected, the relaxation time decreased with an increase in temperature. At a given temperature, there was an increase in relaxation time as a function of polymer concentration, which revealed a progressive reduction in mobility due to polymer addition. The most pronounced effect of polymer concentration was observed with PAA (Figure 8a). For example, at 80 °C, PAA concentrations of 4, 8, and 12% w/w caused ∼3-, ∼66-, and ∼1636-fold increase in relaxation time, respectively. The effect of polymer concentration on the relaxation time was amplified at temperatures close to Tg. At 70 °C, the same PAA concentrations caused ∼5-, ∼168-, and ∼6888-fold increase in relaxation time. The results were qualitatively similar, though they were not as pronounced in the PHEMA and PVP ASDs (Figure 8b,c). To compare the effect of the different polymers, the temperature dependence of the relaxation times was plotted at a fixed polymer concentration of 8% w/w (Figure 8d). As a representative example, let us compare the relaxation behavior at 70 °C. Compared with KTZ (no polymer addition), there was about two orders of magnitude increase in relaxation time of PAA system, while only ∼5- and ∼2-fold increases were observed for PHEMA and PVP systems, respectively. The combined effects of polymer type and concentration on the relaxation time are evident from Figure 9. The increase in relaxation time as a function of polymer concentration was discussed earlier. A dramatic effect of polymer concentration on the relaxation time was observed in the PAA systems. The effect was much less pronounced in PHEMA and was the least in PVP ASDs. Moreover, the differences in the effects of these polymers were amplified at higher polymer concentrations. For example, at 4% w/w polymer concentration, there was a ∼5fold increase in relaxation time of the PAA ASD (compared to KTZ), a ∼1.5-fold increase of the PHEMA ASD, and no increase in the PVP ASD. On the other hand, at 12% w/w polymer concentration, about three orders of magnitude

Figure 9. Relaxation times as a function of polymer concentration at 70 °C.

increase in PAA, an ∼8-fold increase in PHEMA, and a ∼4fold increase in PVP ASDs were observed. The results were qualitatively similar when the polymer concentration was expressed in moles (Figure S4, Supporting Information). Matsumoto et al. studied by DSC the effect of polymer concentration on molecular mobility of indomethacin−PVP ASDs.18 Compared with the mobility of indomethacin, the addition of 5 and 30% w/w polymer (PVP K12) resulted in ∼2and ∼5-fold increase in relaxation times. A similar effect of PVP K12 was observed in nifedipine ASDs. The temperature dependencies of α-relaxation times in the supercooled liquid can be described by the Vogel−Tamman− Fulcher-Hesse (VTFH) equation:

⎛ DT0 ⎞ τ = τ0 exp⎜ ⎟ ⎝ T − T0 ⎠

(2)

where τ is the relaxation time, τ0 is the pre-exponential relaxation factor, and T0 is the zero mobility temperature. D is the strength parameter, an indicator of fragility. The preexponent value (τ0) was set to 10−14 s, which represents the quasilattice vibration period.51 The VTF model (Sigmaplot Systat Software, California, USA) was used to fit the relaxation time data (Figure 8; VTF fit parameters are presented in Table S1, Supporting Information). The calculated dielectric Tg value using the VTF model, assuming a relaxation time of 100 s, was in good agreement with the calorimetric Tg value measured by DSC. The strength parameter (D) of amorphous KTZ obtained from the fit was ∼8, in agreement with the D-value of 5 reported earlier.52 This suggests that KTZ is a fragile glass former. Variable Temperature Powder X-ray Diffractometry (VTXRD). DSC had revealed the onset of KTZ crystallization at ∼109 °C. However, in our XRD experiments, we observed KTZ crystallization when held at 85 °C (Figure 10). The differences in the crystallization inhibitory effect of the three polymers were evident from the VTXRD results. The first evidence of KTZ crystallization was observed at different temperatures, depending on the type of polymer used. In the PVP ASD, the first evidence of crystallization was observed at 90 °C. PHEMA and PAA were more effective crystallization inhibitors with crystallization onset evident at 100 and 105 °C, respectively. Thus, on the basis of both DSC and VTXRD, PAA was most effective in inhibiting KTZ crystallization. The results from our present study established the link between strength of drug−polymer interactions and molecular 3347

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Molecular Pharmaceutics

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Article

ASSOCIATED CONTENT

S Supporting Information *

Plot of change in heat capacity as a function of polymer concentration, plot of predicted and experimental Tg values of PAA ASDs at high polymer concentrations, IR spectrum of PAA and its sodium salt, table of VTF parameters and dielectric Tg obtained from the model fitting of relaxation time data, plot of relaxation times as a function of polymer concentration expressed in moles, structure of an H-bonded, gas-phase dimer of isobutyric acid and N-methylimidazole used for DFT calculations of NMR chemical shielding, and results of DFT calculations of NMR chemical shielding performed using the model system for the interaction between KTZ and PAA. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.5b00333.

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Figure 10. XRD patterns of KTZ and the ASDs subjected to a controlled temperature program. The temperatures at which the powder patterns were obtained are indicated. KTZ crystallization is evident from the appearance of its characteristic peaks.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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mobility. Specific drug−polymer ionic interactions enhanced the physical stability and dissolution of lapatinib, a poorly soluble drug.53 These effects were attributed to the existence of the drug and polymer as an intimate mixture down to a domain size of 95−110 nm. Earlier work by Yoo et al. documented enhancement in miscibility and physical stability brought about by ionic interactions between several crystalline additives and an amorphous polymer.14 We have documented a pronounced reduction in molecular mobility, manifested by orders of magnitude increase in the α-relaxation time, brought about by ionic interactions between KTZ and PAA. Thus, we attribute the effective crystallization inhibition brought about by PAA to the reduction in molecular mobility. Our conclusion is supported by literature report of several orders of magnitude increase in viscosity brought about by ionic interactions and Hbonding in polymers.54−56 In a recent study that used several polymers, the influence of the strength of nifedipine-polymer H-bonding interactions on the molecular mobility and physical stability was investigated. The strongest drug−polymer Hbonding interactions translated to the longest structural relaxation times and the highest resistance to nifedipine crystallization.3

ACKNOWLEDGMENTS The project was partially funded by the William and Mildred Peters endowment fund. Parts of this work were carried out in the Characterization Facility, University of Minnesota, a member of the National Science Foundation-funded Materials Research Facilities Network (www.mrfn.org). Solid-state NMR experiments were carried out at Minnesota NMR center, University of Minnesota. Vishard Ragoonanan, Khushboo Kothari, and Mehak Mehta are thanked for their useful comments.

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REFERENCES

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CONCLUSIONS The importance of the strength of drug−polymer interaction in the stabilization of KTZ in ASDs has been demonstrated. Ionic as well as H-bonding was observed between KTZ and PAA. On the other hand, PHEMA and PVP, respectively, showed Hbonding and dipole−dipole interactions with KTZ. A strong drug−polymer bonding translated to a pronounced reduction in molecular mobility and a delay in crystallization. The strength of drug−polymer interaction, reduction in molecular mobility, and enhancement in physical stability (crystallization inhibition) followed the order: PAA > PHEMA > PVP. In an ionically bonding system (KTZ-PAA), the reduction in mobility was dramatic, as seen by an about two orders of magnitude increase in relaxation time brought about by addition of low (8% w/w) polymer concentration. An increase in strength of drug−polymer interactions, by reducing the molecular mobility, can potentially stabilize ASDs (i.e., delay the onset and reduce the extent of drug crystallization). 3348

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