Application of Solid-State NMR Relaxometry for Characterization and

Article pubs.acs.org/molecularpharmaceutics

Application of Solid-State NMR Relaxometry for Characterization and Formulation Optimization of Grinding-Induced Drug Nanoparticle Keisuke Ueda, Kenjirou Higashi, and Kunikazu Moribe* Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan S Supporting Information *

ABSTRACT: The formation mechanism of drug nanoparticles was investigated using solid-state nuclear magnetic resonance (NMR) techniques for the efficient discovery of an optimized nanoparticle formulation. The cogrinding of nifedipine (NIF) with polymers, including hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP), and sodium dodecyl sulfate (SDS) was performed to prepare the NIF nanoparticle formulations. Then, solid-state NMR relaxometry was used for the nanometer-order characterization of NIF in the polymer matrix. Solid-state NMR measurements revealed that the crystal size of NIF was reduced to several tens of nanometers with amorphization of NIF by cogrinding with HPMC and SDS for 100 min. Similarly, the size of the NIF crystal was reduced to less than 90 nm in the 40 min ground mixture of NIF/PVP/SDS. Furthermore, 100 min grinding of NIF/PVP/SDS induced amorphization of almost all the NIF crystals followed by nanosizing. The hydrogen bond between NIF and PVP led to the efficient amorphization of NIF in the NIF/PVP/SDS system compared with NIF/HPMC/SDS system. The efficient nanosizing of the NIF crystal in the solid state, revealed by the solid-state NMR relaxation time measurements, enabled the formation of large amounts of NIF nanoparticles in water followed by the polymer dissolution. In contrast, excess amorphization of the NIF crystals failed to efficiently prepare the NIF nanoparticles. The solid-state characterization of the crystalline NIF revealed good correlation with the NIF nanoparticles formation during aqueous dispersion. Furthermore, the solid-state NMR measurements including relaxometry successfully elucidated the nanometer-order dispersion state of NIF in polymer matrix, leading to the discovery of optimized conditions for the preparation of suitable drug nanoparticles. KEYWORDS: nanoparticle, grinding, solid-state NMR spectroscopy, NMR relaxation time

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INTRODUCTION Poor water-solubility of a new drug candidate leads to insufficient concentration and subsequently results in poor absorption of the drug in the gastrointestinal tract.1,2 Drug solubilization techniques such as micellar encapsulation,3,4 inclusion complexation with cyclodextrin,5,6 lipid-based particles,7 and cosolvent8 are widely used to improve the drug concentrations in the gastrointestinal tract. However, drug solubilization does not always lead to improved absorption of poorly water-soluble drugs since strong encapsulation of drugs into drug carriers often results in reduced drug permeability through the membrane of the small intestine.9−12 The physical modification of a drug crystal is a promising way to improve the aqueous solubility and dissolution rate of the drug. Amorphization13,14 and polymorphic transformation15 of a drug crystal increases its energy level compared to the intrinsic crystal, leading to improved drug dissolution properties. Nanosizing of a drug crystal increases its surface area and dissolution rate.16−18 Supersaturated drug concentrations can be achieved by aqueous dispersions of these modified drugs. Drug permeability is usually maintained in the supersaturated drug solution compared with the intrinsic drug permeability, in contrast to drug solubilization, and therefore, a significant © XXXX American Chemical Society

improvement in drug absorption is achieved due to the dissolution improvement.9,10,19 Drug dissolution and absorption improvement by drug nanosizing depends critically on the size of the nanoparticles; smaller nanoparticles significantly improve drug dissolution and absorption more than larger ones.17,20 The preparation methods of drug nanoparticles have been widely examined and are based on top-down and bottom-up processes.21 The high-pressure homogenization and media milling are categorized as the top-down process and manufacture drug nanoparticles by fracturing the drug crystal with mechanical stress.22,23 In contrast, an antisolvent precipitation, categorized as the bottom-up process, forms drug nanoparticles by nanoprecipitation from organic solvents in which the drug is dissolved.24,25 Nanoparticles composed only of drugs have been successfully prepared in previous studies.26,27 However, nanoparticles composed of drugs alone are commonly unstable due to precipitation followed by aggregation of drug nanoparticles. Received: October 15, 2015 Revised: February 6, 2016 Accepted: February 8, 2016

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DOI: 10.1021/acs.molpharmaceut.5b00781 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Molecular Pharmaceutics

addition, the dispersion behavior of each grinding mixture in water was investigated based on the drug nanoparticles and supersaturation formations using varying centrifugal force. Finally, the correlation between the elucidated molecular state of the solid formulations and the aqueous dispersion behavior of the poorly water-soluble drug was analyzed to determine the most suitable process for formulating the nanoparticle dispersions.

Hence, various surfactants and polymers have been studied for use as aggregation inhibitors to stabilize the drug nanoparticles in aqueous suspensions.28,29 Currently, methods for the evaluation of drug nanoparticle in solid formulation are limited, and the design of drug nanoparticle formulations, including constitutive substances and preparation conditions, is determined using trial and error processes. The nanometer-order size reduction of drug crystals has the advantage of nanoparticle formulation, and therefore, the process analysis and mechanistic investigation of nanoparticle formation here require the use of nanometer-order, molecular-level evaluation, or both techniques. Although X-ray scattering and differential scanning calorimetry are strong tools for the evaluation of the crystalline properties of drug such as crystallinity, the determination of crystal size is still a serious challenge. Optical microscopy techniques have also been used to directly detect the small drug crystals.30,31 However, the spatial resolution of optical microscopy is limited to approximately 250 nm.32 Therefore, to achieve further resolution of drug crystals, Ricarte et al.33 applied the transmission electron microscopy to detect drug nanocrystal dispersed in polymer matrix. While transmission electron microscopy achieves nanometer-order and high-sensitivity detection of drug crystals, microscopic techniques provide limited information on the molecular state of particles in a particular field of view. The complete evaluation of the dispersion state of a drug overall system is required for the optimization of nanoparticle formulations. Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for molecular-level evaluation and offers complete information on the molecular state of the system. As liquid-state NMR is commonly used in the pharmaceutical field, solid-state NMR techniques are becoming general evaluation methods for solid formulations owing to their sensitivity and resolution enhanced by magic angle spinning (MAS), cross-polarization (CP), and high power decoupling techniques.34 Structural conformation, molecular mobility, and molecular interaction of drug and excipients in solid formulations were previously examined using solid-state NMR measurements.35,36 In particular, NMR relaxation time reflects molecular mobility in two different motional regimes, accessed by either laboratory frame spin−lattice relaxation time (T1) or rotating frame spin−lattice relaxation time (T1ρ). The localized mobility of specific nuclei can be investigated by measuring the NMR relaxation time. Furthermore, the nanometer-order or molecular-level miscibility of drugs and excipients in solid formulations such as solid dispersions was successfully revealed using NMR relaxation time measurements.37,38 In this study, NMR relaxometry was used in the nanometer-order evaluation of drug crystals dispersed in a polymer matrix. Previous studies showed that coground mixtures of poorly water-soluble drug with polymers, such as hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP), and sodium dodecyl sulfate (SDS) led to nanoparticle formation in water.39−41 The polymer functioned as the grinding media, while surfactant not only promoted dispersion into aqueous solution but also stabilized the nanoparticle dispersion. In this study, nifedipine (NIF) nanoparticles were prepared using the cogrinding method. The effects of grinding time and excipients on the molecular state of NIF in the grinding mixture were examined mainly by using solid-state NMR techniques including 13C CP/MAS NMR and NMR relaxation time (T1 and T1ρ of proton) measurements. In

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EXPERIMENTAL SECTION Materials. NIF and SDS were purchased from Wako Chemicals Co., (Tokyo, Japan). HPMC (TC-5E) and PVP (Kollidon 25) were a kind gift from the Shin-Etsu Chemical Co. (Tokyo, Japan) and BASF (Ludwigshafen, Germany), respectively. All other chemicals were of reagent grade. The chemical structures of NIF, HPMC, PVP, and SDS are shown in Figure 1. The morphology of intact HPMC and PVP powder is shown in Figure S1.

Figure 1. Chemical structures of (a) nifedipine (NIF), (b) hydroxypropyl methylcellulose (HPMC), (c) polyvinylpyrrolidone (PVP), and (d) sodium dodecyl sulfate (SDS). Carbon numbering of NIF represents peak assignment in NMR spectra.

Methods. Preparation of Ternary Mixture. A physical mixture (PM) of NIF, polymer, and SDS at a weight ratio of 1:2:1 was prepared by vortexing in a glass vial for 3 min. HPMC and PVP were used as polymer excipients in this study. The PM samples were continuously ground at 50 Hz for 15, 40, and 100 min at room temperature of 25 °C using a vibration rod mill (CMT TI-200, CMT Co., Ltd., Fukushima, Japan) to prepare the ground mixture (GM). Total grinding time of GM was represented in the parentheses following the word “GM”. Powder X-ray Diffraction Measurement. Powder X-ray diffraction (PXRD) measurements were conducted using a Bruker D8 ADVANCE (Bruker AXS, Karlsruhe, Germany) under the following conditions: target, Cu; voltage, 40 kV; current, 40 mA. Scans were performed with a detector step size of 0.02° over an angular range 2θ = 5−30° and counting for 1.5 s per step. Solid-State NMR Measurements. Solid-state NMR measurements were conducted using a 4 mm CP/MAS probe with an ECX-400 NMR system (9.4 T, JEOL Resonance Inc., Tokyo, B


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Figure 2. Powder X-ray diffraction (PXRD) patterns of (left) NIF/HPMC/SDS and (right) NIF/PVP/SDS systems; (a,f) intact NIF, (b,g) PM, (c,g) GM (15 min), (d,i) GM (40 min), and (e,j) GM (100 min). Characteristic peaks of SDS crystal are denoted with asterisks in PXRD patterns of GMs.

Figure 3. 13C CP/MAS NMR spectra of (a) intact NIF, (b,e) GM (15 min), (c,f) GM (40 min), and (d,g) GM (100 min) of (b−d) NIF/HPMC/ SDS and (e−g) NIF/PVP/SDS systems. The characteristic peaks of amorphous NIF are denoted by asterisks.

C


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Figure 4. 13C CP/MAS NMR spectra of (a) intact NIF, (b) intact SDS, (c) GM (15 min), (d) GM (40 min), and (e) GM (100 min) of (black) NIF/HPMC/SDS and (red) NIF/PVP/SDS systems. The spectra of GM were normalized to the SDS peak at around 15 ppm.

Japan). The 13C NMR spectra were acquired using CP and MAS at 15 kHz and two-pulse phase-modulated (TPPM) 1H decoupling sequence at 85 kHz at 20 °C. The pertinent acquisition parameters included relaxation delays of 4−60 s, CP contact time of 1 ms, and 1H 90° pulse of 2.95 μs. All spectra were externally referenced by setting the methyl peak of hexamethylbenzene to 17.35 ppm. The laboratory frame spin−lattice relaxation time (T1) and rotating frame spin−lattice relaxation time (T1ρ) of the proton were measured using an inversion−recovery and a spin-lock sequence, respectively, at spinning rate of 5 kHz at 20 °C. For the relaxation time measurements in the multicomponent system, inversion−recovery and spin-lock sequences followed by CP at the contact time of 1 ms were used to calculate the 1 H-T1 and 1H-T1ρ with high-resolution 13C spectra. Twelve points were set for the τ interval in the inversion−recovery sequence for the curve-fitting to evaluate the 1H-T1. For the 1 H-T1ρ measurements, the delay time in the spin-lock sequence was varied from 0.1 ms to the time required to obtain the decay curve, and the spin locking pulse at 42 kHz was used for all the points. The 1H-T1 and 1H-T1ρ were calculated using the JEOL Delta software ver. 5.04 (JEOL Resonance Inc., Tokyo, Japan). The 1H-T1 and 1H-T1ρ of overlapped peaks were calculated after waveform separation by curve fitting analysis using ALICE 2 software. Characterization of Aqueous GM Dispersion. To prepare the PM and GM dispersions, 20 mg of each mixture was dispersed in 5 mL of distilled water at 25 °C. The PM and GM dispersions were rotated at 50 rpm using a rotor mixer (RKVSD, ATR, Laurel, MD, USA) at 25 °C. The appearance of the GM dispersions was evaluated in a glass vial after a 30 min rotation. The particle size was determined using the dynamic light scattering method with UPA-UT 151 (Nikkiso Co., Ltd., Tokyo, Japan). The PM and GM dispersions after a 30 min rotation were centrifuged at 1000, 5000, and 100000 × g for 30 min at 25 °C. The NIF concentrations in the supernatants of the centrifuged PM and GM dispersions were determined using HPLC.

HPLC Conditions. The sample solutions were diluted with acetonitrile before quantification and were separated using a Shodex ODS column (5 μm, 150 mm × 4.6 mm) at 40 °C. The mobile phase consisted of 50% (v/v) each of acetonitrile and ammonium acetate buffer (pH 6.8), while the injection volume and flow rate were 5 μL and 1 mL/min, respectively. The NIF concentration was determined by measuring the UV absorption at 235 nm.

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RESULTS AND DISCUSSION Solid-State Characterization of GM. Figure 2 shows the PXRD patterns of NIF/HPMC/SDS and NIF/PVP/SDS GMs. Grinding of the PM reduced the characteristic peaks of NIF (Figure S2). The size reduction, amorphization, or both of the NIF crystals decreased their X-ray diffraction.39,42 HPMC and PVP acted as adequate dispersed media for efficient size reduction and amorphization of the NIF crystals following the mechanical stress due to grinding. Comparing HPMC and PVP, the reduction of NIF peaks associated with grinding was larger in the NIF/PVP/SDS system than it was in the NIF/HPMC/ SDS. Furthermore, the PXRD peaks of the NIF crystals almost disappeared in the NIF/PVP/SDS GM (100 min) but not the NIF/HPMC/SDS GM (100 min). PVP induced efficient amorphization or size reduction of NIF crystals or both during the grinding process. Solid-state NMR measurements were performed for the detailed evaluation of the molecular states of NIF. Figure 3 shows the 13C CP/MAS NMR spectra of the intact NIF and GMs in the range of 95−185 ppm. The chemical shift of the NIF peaks, derived from intrinsic NIF crystal, was constant despite the cogrinding with HPMC and SDS. However, the broadened peaks of NIF, which are denoted with asterisks, appeared as the grinding proceeded, especially in the NIF/ PVP/SDS GM (100 min). In a previous study, similar broadened peaks of NIF were observed in the NMR spectrum of amorphous NIF prepared using the melt-quenched method.43 For the comparison, a spray-dried sample of NIF/ HPMC/SDS and NIF/PVP/SDS with the same composition, containing only amorphous NIF, was prepared (Figure S3). D


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Molecular Pharmaceutics The 13C CP/MAS NMR spectrum of the spray-dried sample showed broad peaks of amorphous NIF (Figure S3). It was confirmed that the cogrinding of NIF with polymers induced the amorphization of the NIF crystals. Although part of the NIF crystals was amorphized in the cogrinding process, the intrinsic crystalline form was clearly retained in all the NIF/HPMC/ SDS GMs. On the contrary, almost all the NIF crystal peaks were absent in the 13C CP/MAS spectrum of NIF/PVP/SDS GM (100 min), while the NIF intrinsic crystalline form was clearly retained in the NIF/PVP/SDS GM (15 min) and NIF/ PVP/SDS GM (40 min). NIF/HPMC/SDS GM (100 min) and NIF/PVP/SDS GM (40 min) showed overlapping peaks of amorphous and crystalline NIF. The amount of amorphous NIF in NIF/HPMC/SDS GM (100 min) and NIF/PVP/SDS GM (40 min) was roughly determined based on the comparison of their 13C CP/MAS spectrum with that of the spray-dried ternary complex (Figures S4 and S5). The calculated amount of amorphized NIF in NIF/HPMC/SDS GM (100 min) and NIF/PVP/SDS GM (40 min) was approximately 42% and 37% of the total NIF, respectively. Both NIF/HPMC/SDS GM (100 min) and NIF/PVP/SDS GM (40 min) contained approximately 40% of amorphized NIF with similar crystallinity of NIF. Since NIF/PVP/SDS GM (100 min) showed a broad peak for amorphous NIF and a weak peak for crystalline NIF, the crystalline NIF were more efficiently removed from the NIF/PVP/SDS system than they were from the NIF/HPMC/SDS, in accordance with the results of the PXRD measurements (Figure 2). The entire 13C CP/MAS spectra of intact NIF, intact SDS, and GMs are shown in Figure 4. Cogrinding induced peak broadening of SDS in both NIF/HPMC/SDS and NIF/PVP/ SDS systems with a slight change in the chemical shift of the SDS peaks, which were observed at 10−40 and approximately 70 ppm. The disintegrating crystalline packing of SDS is expected to change the electron density surrounding the 13C atoms of SDS and the chemical shift of the SDS peaks. The line broadening of the SDS peak could be attributed to the wider distribution of isotropic chemical shifts in the same carbons belonging to different molecules in the disordered packing.44,45 In contrast, the peak shape and chemical shift of HPMC were similar between GM and the intact HPMC (Figure S6). The cogrinding with NIF and SDS resulted in very small changes in the chemical environment surrounding HPMC. However, the carbonyl carbon peak of PVP was downfield shifted as cogrinding proceeded (Figure 5), while the chemical shift of the other PVP peaks was almost constant (Figure S7). Similar

chemical shift changes in the carbonyl carbon peak of PVP have been reported in previous studies; NIF formed hydrogen bonds with PVP in the solid dispersion of NIF and PVP, resulting in a downfield shift of the carbonyl carbon peak.38 Cogrinding induced both NIF amorphization (Figure 3) and the downfield shift of carbonyl carbon of PVP (Figure 5), while the changes in peak shape and chemical shift of SDS were not marked among NIF/PVP/SDS GM at different cogrinding times (15−100 min) (Figure 4). The grinding process induced hydrogen bonding between NIF and PVP, leading to changes in the chemical environment surrounding the carbonyl carbon of PVP. In comparison of NIF peaks between NIF/HPMC/SDS and NIF/PVP/SDS systems (Figure 4), the difference in the coground polymer (HPMC or PVP) affected the NIF peakshape as grinding proceeded. In contrast, the peak shape of SDS was similar in both systems. PVP contributed to the transformation of the NIF crystalline state efficiently and selectively compared with HPMC. The molecular interaction between drug and polymer stabilizes the amorphous drug. This interaction can hinder the formation of the drug crystal lattice and the intermolecular interaction between drugs molecules. PVP could stabilize the amorphous state of NIF formed in the grinding process via the strong molecular interaction between PVP and NIF. The difference in the molecular interaction between NIF and each polymer resulted in different levels of efficiency of the amorphization of NIF crystal in the grinding process. Table 1 shows the 1H-T1 and 1H-T1ρ values of NIF, HPMC, PVP, and SDS in each intact and ternary GM. The carbon magnetization decay was evaluated using the inversion− recovery and spin-lock sequence followed by CP to calculate 1 H-T1 and 1H-T1ρ for the multicomponent systems. The NMR relaxation time reflects the molecular mobility of the solid state, influenced by the chemical structure, structural rigidity, temperature, and moisture. HPMC and PVP showed smaller 1 H-T1 values than NIF, indicating the higher mobility of HPMC and PVP emerging from their flexible polymeric structures. On the contrary, a rigid structure in the crystalline state of NIF lowered the NIF mobility of the solid state, leading to a larger 1H-T1 value. The 1H-T1 value of NIF was significantly decreased by cogrinding with HPMC. Although the amorphized NIF peaks were not clearly observed in NIF/ HPMC/SDS GM (15 min) and NIF/HPMC/SDS GM (40 min) (Figure 3), the grinding of NIF crystal should reduce the structural rigidity of NIF crystal, which partially is attributable to the decrease of the 1H-T1 value of NIF. In the solid state, the spin−lattice relaxation time is much longer than spin−spin relaxation time (T2), leading to the persistent retention of excited energy in the spin system before the magnetization was transferred to the magnetic lattice.46,47 This resulted in the propagation of spin energy among neighboring nuclei through the “flip-flop” of the magnetization without any loss of energy, known as spin diffusion. The spin diffusion occurs through the dipolar coupling network in the proton spin bath, where relatively fast relaxing species such as HPMC function as effective relaxation sinks. The cogrinding of NIF with HPMC induced the dispersion of NIF crystal into HPMC and the formation of the dipole−dipole interaction between NIF and HPMC protons, resulting in the decrease of 1H-T1 value of NIF in the GM samples. The increase in grinding time with HPMC further reduced the 1H-T1 value of the NIF crystal. The spin− lattice relaxation time of different protons in a sample is comparable owing to the spin diffusion effect. The spin

Figure 5. 13C CP/MAS NMR spectra of (a) intact PVP, (b) GM (15 min), (c) GM (40 min), and (d) GM (100 min) of NIF/PVP/SDS system. Dotted line represents chemical shift of carbonyl carbon of intact PVP. E


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Table 1. Proton Laboratory Frame Spin−Lattice Relaxation Time (1H-T1) and 1H-Rotating Frame Spin−Lattice Relaxation Time (1H-T1ρ) of NIF, HPMC, PVP, and SDS in Each Intact and GM at 20°C and Spinning Rate of 5 kHz; 1H-T1 and 1H-T1ρ Are Presented as Averaged Values (±10%) 1

1

H-T1 (s)

NIF intact NIF intact SDS intact HPMC intact PVP NIF/HPMC/SDS system

NIF/PVP/SDS system

NIF

HPMC

PVP

1.3

104.9 8.8

2.4 GM (15 min) GM (40 min) GM (100 min) GM (15 min) GM (40 min)

b1

3.3a 2.2a 1.8a 1.7b 2.8a 2.3a 2.2b 2.2b

SDS

519.6a

1.5 1.5 1.7

10.3 1.6 1.7 1.7

2.2 2.2

1.8 1.9

2.3

2.4

160.3a 118.9a 75.8a 9.4b 117.0a 64.8a 10.9b 11.6b

7.8 8.2 8.1

49.3 42.5 38.5 10.0 10.6

44.5 37.2

11.3

36.0

H-T1 and 1H-T1ρ value of amorphous NIF.

SDS GM (40 min), while that of SDS was slightly different. The domain size of the mixture of NIF and PVP in the NIF/ PVP/SDS GM (40 min) was expected to be less than 90 nm, as calculated using eq 1. In addition, the 1H-T1ρ value of crystalline NIF in the NIF/PVP/SDS GM (40 min) was similar to that in the NIF/HPMC/SDS GM (100 min). Since the 1H-T1ρ values of HPMC and PVP were similar, the 40 min grinding with PVP and 100 min grinding with HPMC similarly averaged the spin−lattice relaxation time of NIF by the spindiffusion. The dispersed crystalline sizes of NIF in each polymer matrix should be several tens of nanometers in both NIF/PVP/SDS GM (40 min) and NIF/HPMC/SDS GM (100 min). Furthermore, the amorphous NIF in NIF/PVP/SDS GM (40 min) showed similar 1H-T1ρ values as PVP of around 11 ms, indicating that amorphous NIF was miscible with PVP at the domain size of approximately 6 nm. NIF/PVP/SDS GM (40 min) contained the nanocrystal and amorphous dispersion of NIF in PVP. Further grinding of NIF/PVP/SDS resulted in the amorphization of almost NIF crystals in NIF/PVP/SDS GM (100 min) (Figure 3). PVP effectively amorphized NIF followed by size reduction of NIF crystals compared with HPMC. Suspension-State Characterization of GM Dispersion. Figure 6 presents the suspension appearance of the GM dispersions after rotor mixing for 30 min at 25 °C. All the GM dispersions showed the yellow color of NIF; however, the suspension turbidity differed among the dispersions. The NIF/ HPMC/SDS GM (100 min), NIF/PVP/SDS GM (40 min), and NIF/PVP/SDS GM (100 min) dispersions showed a

diffusion effect on changing the relaxation time depends on the miscibility among the different components, where the spin diffusion occurs. The progression of the size-reduction of the NIF crystals promoted their mixing with HPMC in the small domain size. Finally, the 1H-T1 value of NIF crystal was comparable to that of HPMC in the NIF/HPMC/SDS GM (100 min). Similar phenomena of averaging relaxation time among different components were previously reported for the polymer blend and solid dispersion,38,48 which is an index of the homogeneity of the different components in an nanometerorder size. When the spin-relaxation time was completely averaged among the different components, the effective domain size where spin diffusion occurs can be estimated using eq 1.49

6Dt

SDS

1.5

H-T1 and 1H-T1ρ value of crystalline NIF.

L=

PVP

25.7a

GM (100 min) a1

HPMC

H-T1ρ (ms)

(1)

where L is average diffusion path length occurring in time t and D is the spin diffusion constant. The spin relaxation time, 1H-T1 and 1H-T1ρ, was equal to the available time of the spin diffusion (t). The D value of the typical polymer below the glass transition temperature was approximately 6 × 10−16 m2/s.48,50 From eq 1, both crystalline and amorphous NIF were homogeneously mixed with HPMC in the domain size of approximately 80 nm in the NIF/HPMC/SDS GM (100 min). The high miscibility of the crystalline NIF and HPMC indicated that cogrinding nanosized the NIF crystals dispersed in HPMC. In contrast to the averaging of the 1H-T1 value in the NIF/HPMC/SDS GM (100 min), the 1H-T1ρ value of NIF crystal was much higher than that of HPMC. The domain size of NIF crystal and HPMC in NIF/HPMC/SDS GM (100 min) was larger than the effective spin diffusion length of around 5 nm, which was calculated using eq 1 with the 1H-T1ρ value of HPMC.50 Therefore, most of the NIF crystals dispersed in HPMC matrix should be several tens of nm in the NIF/ HPMC/SDS GM (100 min). On the contrary, amorphous NIF represented an 1H-T1ρ value similar to that of HPMC in NIF/ HPMC/SDS GM (100 min), indicating homogeneous mixing of amorphous NIF with HPMC (domain size of approximately 5 nm). The cogrinding process induced the formation of solid dispersion of NIF and HPMC followed by the nanosizing of NIF crystal in HPMC. The cogrinding of NIF with PVP and SDS also reduced the 1 H-T1 value of NIF. The 1H-T1 value of both crystalline and amorphous NIF was similar to that of PVP in the NIF/PVP/

Figure 6. Appearance of GM dispersions in water after rotation mixing at 25 °C. F


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Molecular Pharmaceutics slightly paler color than the other GM dispersions. The particle size distribution of the GM dispersion was determined using dynamic light scattering (Figure 7). Cogrinding of NIF with the

Figure 8. NIF concentration in PM and GM dispersions centrifuged at (blue) 1000, (red) 5000, and (green) 100000 × g followed by rotation mixing at 25 °C (n = 3, mean ± SD). The dose concentration of NIF was 1000 μg/mL.

Figure 7. Particle size distribution of (a) GM (15 min), (b) GM (40 min), and (c) GM (100 min) dispersions of NIF/HPMC/SDS system, and (d) GM (15 min), (e) GM (40 min), and (f) GM (100 min) dispersions of NIF/PVP/SDS system in water after rotation mixing at 25 °C.

polymer and SDS induced nanoparticle formation, while the intrinsic NIF crystal contained particles in micrometer range (Figure S8). However, dynamic light scattering underestimates smaller nanoparticles when the solution contains particles of varying sizes, and quantitative evaluations of the size and amount of nanoparticles are rarely achieved. Therefore, we evaluated the amount of NIF nanoparticles in each size fraction using a centrifugation process. After a 30 min rotation, the GM dispersions were centrifuged at 1000 and 5000 × g, and then the NIF concentrations in the supernatants were determined using HPLC (Figure 8). Ultracentrifugation at 100000 × g was performed to determine the dissolved concentration of NIF after removal of the nanoparticles. The PM dispersions showed an almost constant value of NIF concentrations independent of the centrifugation force. Almost all the NIF was dispersed as large precipitations of the intrinsic crystal form in the PM dispersion of both NIF/ HPMC/SDS and NIF/PVP/SDS systems. In contrast, the NIF concentrations of the GM dispersions after centrifugation were different depending on the centrifugation force, especially for the NIF/HPMC/SDS GM (100 min) and NIF/PVP/SDS GM (40 min) dispersions. The particle size distribution of these suspensions after centrifugation at 1000 and 5000 × g are shown in Figure 9. The suspensions centrifuged at 1000 and 5000 × g showed a size distribution with a median size of approximately 150 and 80 nm, respectively, for both the NIF/ HPMC/SDS GM (100 min) and NIF/PVP/SDS GM (40 min) dispersions. The GM dispersions centrifuged at 1000 × g contained dissolved NIF and its nanoparticles that were a 100

Figure 9. Particle size distribution of (a−c) NIF/HPMC/SDS GM (100 min) dispersions and (d−f) NIF/PVP/SDS GM (40 min) dispersions after rotation mixing at 25 °C. Centrifugation was conducted at (b,e) 1000 and (c,f) 5000 × g for 30 min before particle size distribution measurements.

and several tens of nanometers or less, while those centrifuged at 5000 × g contained the dissolved NIF and its nanoparticles of several tens of nanometers or less. The progressive grinding also increase the NIF nanoparticles, indicated by the NIF concentrations in the GM dispersions centrifuged at 1000 and 5000 × g in the NIF/HPMC/SDS system (Figure 8). The extension of the grinding time increased the concentration of the nanoparticulated NIF. In the aqueous dispersion of NIF/HPMC/SDS GM (100 min), the NIF concentrations after centrifugation at 1000 and 5000 × g were significantly increased to 835 and 297 μg/mL, respectively. The G


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Figure 10. Schematic illustration of effect of grinding process on aqueous dispersion properties of NIF.

NIF/PVP/SDS GM (40 min) dispersion centrifuged at 5000 × g attained 252.7 μg/mL, indicating the efficient formation of NIF nanoparticles of several tens of nanometers. However, further grinding of the NIF/PVP/SDS decreased the NIF nanoparticles to several tens of nanometers; the NIF concentration in the GM dispersion centrifuged at 5000 × g was 63.5 μg/mL for NIF/PVP/SDS GM (100 min), which was 4-fold lower than that of GM (40 min). The 40 min grinding was the optimum condition for the NIF nanoparticle formation in the NIF/PVP/SDS system compared with the 100 min grinding. The NIF/HPMC/SDS GM (100 min) formed the NIF nanoparticles more efficiently than the NIF/HPMC/SDS GM (40 min). Therefore, the optimum grinding time for the NIF nanoparticle formation strongly depended on the coground polymer. The NIF concentration in the NIF/PVP/SDS PM dispersion ultracentrifuged at 100,000 × g was 19.9 μg/mL and higher than the NIF solubility (Figure 8). The solubilization effect of PVP and SDS increased the NIF concentration more efficiently than that of HPMC and SDS (6.9 μg/mL). The NIF/PVP/ SDS GM dispersions further increased the dissolved NIF concentrations compared with the PM dispersion; the NIF concentrations in the solutions ultracentrifuged at 100000 × g were 38.4, 51.5, and 41.5 μg/mL for GM (15 min), GM (40 min), and GM (100 min) dispersions of the NIF/PVP/SDS system, respectively (Figure S9). Similar to the NIF/HPMC/ SDS system, the amorphization or size reduction of NIF crystals or both followed by cogrinding with PVP and SDS led to NIF supersaturation. It is noteworthy that the dissolved concentration of NIF in the NIF/PVP/SDS GM (40 min) dispersion was 51.5 μg/mL, although further grinding reduced the dissolved NIF concentration to 41.5 μg/mL in the NIF/ PVP/SDS GM (100 min) dispersion. The highest concentration of dissolved NIF in NIF/PVP/SDS GM (40 min) dispersion was likely derived from the maintenance effect of

cogrinding of NIF crystals with HPMC and SDS induced the aqueous dispersion of a large amount of NIF nanoparticles. The dissolved concentrations of NIF, which was determined by ultracentrifugation at 100000 × g, increased with the progress of cogrinding with HPMC and SDS (Figure S9); the dissolved concentration of NIF was 9.8, 11.4, and 17.9 μg/mL in the GM (15 min), GM (40 min), and GM (100 min) dispersions of NIF/HPMC/SDS system, respectively. The dissolved concentrations of NIF in the GM dispersions were higher than that in the NIF/HPMC/SDS PM dispersions at 6.9 μg/mL. The solubilization effect of HPMC and SDS increased the NIF concentration in the NIF/HPMC/SDS PM dispersions compared with the NIF solubility (5.6 ± 0.3 μg/mL, water, 25 °C). Furthermore, the increase in the dissolved NIF concentration of the GM dispersions indicated the formation of NIF supersaturation. Solid-state NMR measurements revealed that cogrinding with HPMC and SDS reduced the crystalline size of NIF and subsequently led to NIF amorphization. Drug amorphization has a considerable advantage of enhancing the dissolution properties of drugs, leading to drug supersaturation. The crystallization of drug from the drug-supersaturated solution hinders the maintenance of a high supersaturated level of the drug. HPMC inhibited drug crystallization from the supersaturated solution,51 and nanoparticle existing in the aqueous solution also prolonged the drug-supersaturated state.52 Since most of the NIF existed as small-sized NIF nanoparticles in the NIF/HPMC/SDS GM (100 min), the NIF supersaturated solution formed by dissolving the partially amorphized NIF in the NIF/HPMC/SDS GM (100 min) was effectively maintained. The cogrinding with PVP and SDS significantly increased the NIF concentrations in the GM dispersion centrifuged at 1000 and 5000 × g (Figure 8). A mere 15 min grinding of the NIF/ PVP/SDS increased the NIF concentrations to 398 and 108 μg/mL in the GM dispersions centrifuged at 1000 and 5000 × g, respectively. Furthermore, the NIF concentration in the H


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the different dispersed states of the NIF crystal in each polymer matrix through grinding. The NIF crystals in the NIF/HPMC/ SDS GM (100 min) and NIF/PVP/SDS GM (40 min) were dispersed in HPMC and PVP matrix in the domain size less than 80−90 nm. PVP effectively fractured the NIF crystal, leading to nanosizing of NIF crystal in the polymer matrix, compared with HPMC. HPMC required additional grinding time to attain the nanosizing of NIF crystal to several tens of nanometers in HPMC matrix. The efficient nanosizing of the NIF crystal in polymer matrix in solid state directly led to the formation of a considerable amount of NIF nanoparticles in the NIF/HPMC/SDS GM (100 min) and NIF/PVP/SDS GM (40 min) dispersions. The solid-phase nanosizing of the NIF crystals was effective for the formation of more and smaller NIF nanoparticle dispersions in the water than in the liquid-phase transformation of the dissolved NIF from amorphized NIF. These results strongly indicate that the formation of a large amount of small nanoparticle requires controlling the nanosizing of the NIF crystal in the polymer matrix to several tens of nanometers without excessive amorphization in the solid state.

drug supersaturation due to the existence of large amounts of NIF nanoparticles of several tens of nanometers or less. Mechanistic Elucidation of Nanoparticle Formation Considering the Solid-State Characterization. The cogrinding of NIF with the polymer and SDS led to aqueous dispersion of NIF nanoparticles and further supersaturation of NIF. Figure 10 presents the schematic illustration of the formation mechanism of the drug nanosuspensions affected by the solid-state property. The present study demonstrated that an efficient NIF nanoparticle formation, especially with several tens of nanometers, requires the selection of an adequate coground polymer and grinding time. The efficient NIFnanoparticle formations can be derived from the solid-phase modification of NIF crystal or liquid-phase transformation of the dissolved NIF, or both. In a previous study, the complete amorphization of a drug in a polymer matrix induced the complete dissolution of the amorphous drug in an aqueous solution as well as drug supersaturation. 52 Since the precipitation of the micrometer-order drug occurred following the dissolution of the amorphous drug, the drug nanoparticles were barely formed from the supersaturated solution.52 In order to elucidate the effect of NIF amorphization in the grinding process on the nanoparticles formation in the GM dispersion, cryogenic grinding was performed for the NIF/HPMC/SDS system. The grinding temperature can affect the mechanical force exerted by grinding,53 leading to the different efficiency levels of the amorphization of NIF crystals by grinding. In addition, drug amorphization in a grinding process was shown to proceed more efficiently at the lower temperature.54 Cryogenic grinding of NIF with HPMC and SDS using liquid nitrogen induced further reduction of NIF crystalline peaks in 13 C CP/MAS NMR spectrum owing to NIF amorphization (Figure S10), indicating the efficient amorphization of NIF in NIF/HPMC/SDS cryogenic-ground mixture (cryo-GM) (100 min) compared to that in NIF/HPMC/SDS GM (100 min). The cryogenic grinding further amorphized NIF mainly by hindering the solid-phase recrystallization via the heat and force of the grinding process. In the comparison with NIF/HPMC/ SDS GM (100 min), the aqueous dispersion of NIF/HPMC/ SDS cryo-GM (100 min) slightly increased the concentrations of the NIF nanoparticles. The NIF concentrations after centrifugation at 1000 and 5000 × g were 185 and 28 μg/mL in the NIF/HPMC/SDS cryo-GM (100 min) dispersion, while they were 835 and 297 μg/mL in the NIF/HPMC/SDS GM (100 min) dispersion, respectively (Figure S11). The disadvantage of NIF amorphization in the formation of NIF nanoparticle dispersion can be also observed with the NIF/ PVP/SDS system. 13C CP/MAS NMR measurements indicated that almost all of the NIF was amorphized by the 100 min grinding with PVP and SDS. The excessive grinding of NIF/ PVP/SDS led to NIF amorphization, followed by nanosizing of the NIF crystal, resulting in the reduction of NIF nanoparticle formation with several tens of nanometers in aqueous dispersion; the NIF concentrations in the GM dispersions centrifuged at 5000 × g were 252.7 and 63.5 μg/mL for NIF/ PVP/SDS GM (40 min) and NIF/PVP/SDS GM (100 min), respectively (Figure 8). The amorphization of NIF in the ternary complex could not efficiently work for the NIF nanoparticle formation. In contrast, the present study strongly indicated that the effective nanosizing of NIF crystal without excess amorphization contributed to the formation of the NIF nanoparticles dispersion. The relaxation time measurements clearly revealed

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CONCLUSIONS The solid-state NMR measurements revealed that the cogrinding of NIF crystal with the polymer, including HPMC and PVP, and SDS significantly reduced the NIF crystal size. The size reduction of the NIF crystals led to their homogeneous mixing with HPMC or PVP in the domain size of 80−90 nm or less. HPMC required further grinding to attain similar homogeneity with the NIF compared with PVP. Further grinding of NIF with PVP resulted in the amorphization of most of the NIF followed by nanosizing of the NIF crystals. The excess amorphization of NIF in the ternary complex failed to form the NIF nanoparticles of several tens of nanometers in the aqueous dispersion. The effective size reduction of the NIF crystal in the solid state without excess amorphization achieved the NIF nanosuspension formation followed by the polymer dissolution. These results suggest that the dispersion properties of drug in polymer matrix, including the crystallinity and domain size of the dispersed drug crystals, directly correlated with the nanoparticle-formation efficiency during aqueous dispersion. Therefore, the direct monitoring of the molecular state of a solid drug based on solid-state NMR techniques including relaxometry could be a powerful tool for the optimization of drug nanoparticle formulations.

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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.5b00781. Morphology of intact HPMC and PVP by scanning electron microscopy (SEM); powder X-ray diffraction (PXRD) patterns of intact samples; 13C CP/MAS NMR spectra; NIF concentration (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel: +81-43-226-2865. Fax: +81-43-226-2867. E-mail: [email protected]. Notes

The authors declare no competing financial interest. I


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ACKNOWLEDGMENTS This study was partly supported by the Research on Development of New Drugs from Japan Agency of Medical Research and Development (AMED), the Grants-in-Aid for Scientific Research (C) (JSPS, 15K07885) from the Japan Society for the Promotion of Sciences, the Hosokawa Powder Technology Foundation, and the Uehara Memorial Foundation. We also thank the Shin-Etsu Chemical Co., (Tokyo, Japan) for the gift of HPMC and BASF (Ludwigshafen, Germany) for the PVP.

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Application of Solid-State NMR Relaxometry for Characterization and

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