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The Binary System of Ibuprofen-Nicotinamide Under Nanoscale Confinement: From Cocrystal to Coamorphous State
Accepted Manuscript The binary system of ibuprofen-nicotinamide under nanoscale confinement: from cocrystal to coamorphous state Yanping Bi, Deli Xiao, Shuai Ren, Shuyan Bi, Jianzhu Wang, Fei Li PII:
S0022-3549(17)30442-2
DOI:
10.1016/j.xphs.2017.06.005
Reference:
XPHS 848
To appear in:
Journal of Pharmaceutical Sciences
Received Date: 27 March 2017 Revised Date:
23 May 2017
Accepted Date: 8 June 2017
Please cite this article as: Bi Y, Xiao D, Ren S, Bi S, Wang J, Li F, The binary system of ibuprofennicotinamide under nanoscale confinement: from cocrystal to coamorphous state, Journal of Pharmaceutical Sciences (2017), doi: 10.1016/j.xphs.2017.06.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The binary system of ibuprofen-nicotinamide under nanoscale confinement: from cocrystal to coamorphous state
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School of Pharmaceutical Sciences, Taishan Medical University, No. 619,
Changcheng Road, Tai’an, 271016, P.R. China
Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of
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Yanping Bi*,1, Deli Xiao 2, Shuai Ren 3, Shuyan Bi4, Jianzhu Wang1 , Fei Li1
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Education, China Pharmaceutical University, Nanjing, 210009, China
Graduate School, Taishan Medical University, No. 619, Changcheng Road, Tai’an,
271016, P.R. China. 4
Department of Ultrasound, Zibo Hospital of PKU Healthcare Industry Group , No.2,
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Xishanwu Street, Zibo, 255069, P.R. China. * Corresponding author. E-mail address: [email protected]; Tel/Fax:
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+8605386229751
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Abstract Coamorphous systems have gained success in stabilizing amorphous drugs and improving their solubility and dissolution. Here we proposed to confine a binary mixture of drug and coformer (CF) within nanopores to obtain a nano-confined coamorphous (NCA) system. For proving feasibility of this
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proposal, a poorly water-soluble drug (ibuprofen, IBP) and a frequently used pharmaceutical CF (nicotinamide, NIC) were loaded into nanopores of mesoporous silica microspheres (MSMs). The solid state of NCA system was characterized by differential scanning calorimetry, X-ray powder diffraction,
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infrared spectrum and solid state nuclear magnetic resonance. With large numbers of nanopores, MSMs appears to be a feasible carrier to transform a cocrystal system into co-amorphism by nanoscale
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confinement. Benefiting from both nanoscale confinement and CF, the NCA system of IBP achieved synchronic increase in dissolution properties and physical stability. Consequently, the NCA strategy is effective in achieving co-amorphous state and offers a promising alternative for formulating poorly water-soluble drugs.
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1. Introduction
Advanced drug discovery approaches often lead to the identification of poorly water-soluble drugs which face great challenges in formulating oral and transdermal dosage forms. In order to surmount the solubilization/dissolution bottleneck, several strategies, such as cocrystal, amorphous and coamorphous
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systems, have been applied to achieving the supersaturation state of drug solution [1, 2]. Pharmaceutical cocrystal is a structure in which an active pharmaceutical ingredient (API) and a neutral
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small-molecule coformer (CF) are incorporated within the same crystalline lattices in a specific stoichiometric amount. The CF can be another API but not a solvent molecule. Physicochemical properties of cocrystals of a given drug depend strongly on the structure of CF; so not every cocrystal form will deliver an improvement in dissolution properties relative to that of original API [3]. Amorphous drugs show a higher apparent solubility and dissolution rate than their crystalline counterparts due to the higher energetic state that does not require the crystal lattice to be broken upon dissolution. However, a pure amorphous API is thermodynamically unstable and prone to recrystallize during storage. The most commonly used strategy to suppress recrystallization of amorphous APIs is to
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[5]
[4]
. Recently, mesoporous silica has gained considerable success
. Once a drug is confined within rigid nanopores of the mesoporous
silica, the size of crystal nuclei will be limited. And if the nanopores are smaller than the critical nucleus size of the drug molecule, the nucleation will be inhibited, so the amorphous state is preserved .
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[6-8]
Besides, coamorphous strategy has also been used to stabilize amorphous drugs. As a special case of amorphous systems, coamorphous system is usually defined as the amorphous binary system of two drugs or a drug and a small molecule CF
[9]
. If the proper CF has been selected, evaporating the
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drug-CF solution will be enough to induce a coamorphous system because, to a certain extent, the CF itself can inhibit crystallization [10]. However, some modified methods, such as low-temperature milling and spray-drying
[12]
, are still absolutely necessary due to the fact that a direct evaporation
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[11]
procedure is more likely to result in a crystalline/co-crystalline system rather than a coamorphous system if the CF is not properly selected. Therefore, the CF selection work for a coamorphous system might be labor-intensive.
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Since confining a single drug in nanopores of mesoporous silica leads to amorphization, confining a cocrystal binary system (API&CF) in nanopores will possibily bring about a coamorphous system. For proving feasibility of this proposal, an acceptable pharmaceutical CF, also a frequently used water-soluble hydrotrope, namely nicotinamide (NIC), and a poorly water-soluble drug, namely
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ibuprofen (IBP), were synchronically loaded into mesoporous silica microspheres (MSMs). The obtained product differs from common bulk coamorphous system in its nanoscale confinement, which
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can be referred to as nano-confined coamorphous (NCA) system. The NCA system, together with amorphous IBP, IBP-NIC cocrystal and pure IBP drug substances, was investigated for its solid-state, dissolution rate and kinetic solubility.
2. Materials and methods 2.1 Materials Waterglass (WG, with a modulus of 3.3; Na2O, 8.3%; SiO2, 26.5%), Span-80, Tween-80 and NIC (99%) were purchased from Qingdao Usolf Chemtech Co.,Ltd (Qingdao, China). Ibuprofen (98%) was
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ACCEPTED MANUSCRIPT supplied by Wuhan Biocause Pharmaceutiacl Co., Ltd (Wuhan, China). Other Chemicals such as petroleum ether (boiling range 60~90oC), sucrose (analytical reagent), methanol (HPLC grade) and ammonium bicarbonate (NH4HCO3, analytical reagent) were purchased from Sinopharm Chemical Reagent Co., Ltd (Shanghai, China).
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2.2 Preparation of mesoporous silica microspheres The preparation of MSMs has been described in our previous report
[13]
. Here, 4g of WG was
dissolved in 6 g of sucrose solution (50%, w/w). Then 20 mL of petroleum ether solution of Span 80 (5%, w/v) was added into the WG solution with stirring for 1 min. Then the mixture was emulsified for
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2 min using a homogenizer (Heidolph DIAX 900) with 8000 rpm to obtain an emulsion (W/O). Finally, the emulsion was poured into 100 mL of an aqueous solution containing NH4HCO3 (15.8%, w/v) and
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Tween 80 (0.5%, w/v) and stirred for 1h for the formation of MSMs. The solid product was recovered, washed with distilled water and ethanol alternately, and air-dried at room temperature. 2.3 Preparation of co-evaporated solid products of IBP-NIC
IBP (2 mmol) and NIC in various molar ratios (2:1, 1:1 and 1:2) were dissolved in 5 mL ethanol at
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room temperature. The resulting clear solutions were allowed for evaporation in a crystallizing dish. After 24 h, solid products containing IBP-NIC of 2:1, 1:1 and 1:2 formed. 2.4 MSMs drug-loading procedure
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NCA system, amorphous IBP and amorphous NIC were prepared also by solvent evaporation method. Briefly, 1:1 mixture of IBP (2 mmol) and NIC (2 mmol) were dissolved in ethanol to obtain
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2.5 g of stock solution. Then 0.8 g of MSMs was suspended in the stock solution under supersonication. The suspension was centrifuged (4000 rpm, 1 min) and the supernatant was completely removed. Finally, the precipitate was dried at room temperature for 24 h to obtain NCA system. By the same procedure, MSMs were respectively immersed into IBP solution and NIC solution to obtain amorphous IBP and amorphous NIC. 2.5 Characterization of drug delivery systems The morphology of NCA system and blank MSMs were studied by a scanning electron microscope (SEM, Quanta 200 FEG, FEI Co., USA) at an acceleration voltage of 20 kV without any coating
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outgassed under high vacuum for 15 min at room temperature. The specific surface area was determined according to the BET method, and the pore size distribution was determined from adsorption branch of isotherm using the Barrett-Joyner-Halenda (BJH) method. The total pore volume
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was determined from the amount adsorbed at a relative pressure of 0.99.
The X-ray powder diffraction (XRPD) patterns were recorded on a D8 Advance X-Ray
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Diffractometer (Bruker-AXS, USA) using CuKα monochromatized radiation at 40 kV, 40 mA. The step scan mode was performed with a step size of 0.02° at a rate of 2°/min.
The thermal properties of powders were studied using a TA Instruments Q-2000 differential scanning calorimetry (DSC). The system was calibrated using indium and an empty pan was used as reference. Typically, 5 mg samples were placed on non-hermetic aluminium pans. Samples were analyzed at a
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heating rate of 10 ºC/min from 30 to 150 ºC under a constant flow of nitrogen. An IRAffinity-1S Fourier Transform Infrared (FT-IR) Spectrophotometer (Shimadzu Corporation, Kyoto, Japan) was employed for recording the IR spectra of samples. Typically, 4 mg of each sample
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was mixed with 100 mg KBr, compressed into tablets and scanned from 400 cm−1 to 4000 cm−1 with a spectral resolution of 4 cm−1. 13
C nuclear magnetic resonance (NMR) experiments were performed using Bruker
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Solid-state
Avance 400 at Larmor frequencies of 400 MHz at 298K. The CP/MAS experiments were carried out using a double-tuned CP/MAS probe equipped for 4 mm outer diameter rotors, a spin rate of 12.5 kHz, 4096 scans. The spectra were referenced to an external sample of methylene carbon of adamantane at 38.48 ppm. 2.6 Drug loading efficiency Drug loading efficiency was determined by adding 50 mg of NCA or amorphous IBP in 250 ml ethanol with stirring for 2 h. Then 5 mL of the supernatant was filtered through a 0.22-µm nylon
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(w/v) aqueous phosphoric acid-methanol (20:80) at the detection wavelength of 220 nm. The flow rate was 1.0 ml/min at room temperature. Ethanol solutions of IBP were used as standard solutions to draw the standard curve. In the concentration range of 1.52~381 µg/ml, the concentration of IBP (Y) correlated well to its peak area (X): Y= 0.00003237X-0.4448 (r = 0.9998, n = 3).
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2.7 Dissolution rate
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Dissolution profiles of the four samples, 30 mg of IBP, 48 mg of cocrystal, 85 mg of amorphous IBP and 170 mg of NCA system, were tested using a dissolution testing instrument (ZRS-8G, Tianda Tianfa Technology Co., Ltd., Tianjin, China). In each test, 500 mL of aqueous solution of Tween 80 (0.1%, w/v) was first placed in the vessel and allowed to come to 37°C before the sample was added. The paddle rotational speed was 100 rpm. At each predetermined time (5, 15, 30, 45, 60, 90, 120 150, 180,
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240 and 400 min), a 5 ml sample was withdrawn and passed through a 0.22-µm syringe filter. Then the IBP concentration was determined by HPLC-UV method (2.6).
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2.8 Kinetic solubility
For kinetic solubility studies of the systems, the equivalent of 50 mg IBP was used employing a
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magnetic stirring speed of 100 rpm and the temperature was maintained at 37 ºC. The dissolution medium was 100 mL of distilled water. As a comparison, amorphous IBP was also tested in an aqueous solution containing 29.6 mg of NIC (because the NCA system used here also contains 50 mg of IBP and 29.6 mg of NIC). Sampling was performed at 5, 10, 20, 30, 60, 90, 120, 150, 180, 210 and 240 min and the withdrawn suspension was filtered through a 0.22-µm syringe filter. The first 4 mL of filtrate was discarded and subsequent filtrate was collected. Then 500 µL of the subsequent filtrate was pipetted accurately into a 1.5 ml centrifuge tube and diluted with equivoluminal aqueous solution of Tween 80 (0.2%, w/v). Then the drug concentration was determined by HPLC-UV method (2.6).
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3. Results and Discussion 3.1 Characterization of MSMs The SEM image of MSMs (Fig. 1a) reveals a spherical morphology with a size ranged from 5 to 15 µm in diameter. Type IV isotherm (Fig. S1, Supporting Information), as well as the SEM image,
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indicates the presence of large amounts of mesopores in MSMs. An average pore diameter of 16.1 nm (Fig. S2a, Supporting Information) and a total pore volume of 1.67 cm3/g imply the potential of MSMs as drug carrier for delivery of both small and large molecule drugs. The large specific surface area (590
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m2/g) paves the way for rapid drug dissolution. After the loading of 1:1 IBP-NIC, the nanopores of MSMs were partially filled and became invisible in SEM image (Fig. 1b), correspondingly, the specific
5.19 nm (Fig. S2b) and 0.61 cm3/g.
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surface area, the average pore diameter and the total pore volume respectively decreased to 407 m2/g,
3.2 Characterization of drug delivery systems
Fig. 2 presents the XRPD patterns of co-evaporated solid products of IBP-NIC. The 1:1 co-evaporated product shows different characteristic peaks from the drug and CF (Fig. 2d), so its
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cocrystal state can be confirmed, plus the single melting peak at 94.6oC in DSC curve (Fig.3b). However, the patterns of 2:1 co-evaporated product shows the representative peaks of IBP (Fig. 2c), indicating the individual phase of remaining IBP. Similarly, the 1:2 co-evaporated product presents
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some remaining NIC (Fig. 2e).
After being loaded into nanopores of MSMs, the binary mixture of 1:1 IBP-NIC and the pure IBP
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show neither typical melting point in DSC curve (Fig. 3c, e) nor diffraction peaks in XRPD pattern (Fig. 4b, c), which indicates their amorphous state. The formation of amorphous/coamorphous type results from the nanoscale confinement rather than the addition of NIC, so the MSMs-loaded binary system of 1:1 IBP-NIC can be referred to as NCA system. Microscope image of the NCA system did not show any crystalline solid outside MSMs (Fig. 1), so we can conclude that IBP and NIC were deposited in nanopores. After 45 days of storage at 60oC, small crystalline peaks might be observed on the amorphous IBP pattern (Fig. 4d) while the NCA system remained unchanged (Fig. 4e), proving that incorporating a
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cm-1 and 3182 cm-1, respectively; the C=O stretching peak of IBP also shifted from 1721 cm-1 to 1707 cm-1. Those two variations indicate the hydrogen bond between the carboxyl group of IBP and the acylamino group of NIC in cocrystal system. The two peaks at 1506 cm-1(IBP) and 1485 cm-1(NIC), representing the skeleton vibrations of the aromatic rings, merged into single one (1516 cm-1) in
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cocrystal system, which demonstrated the π-π interaction between IBP and NIC molecule. Obviously, the NCA system exhibits the same spectrum characteristics with cocrystal system. The similarity
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between IR spectra of NCA system and that of cocrystal system provides an indirect proof that IBP-NIC interaction also exists in NCA system, hence confirms the homogeneity at molecular level and the coamorphous state of NCA system.
Solid-state 13C NMR spectra (Fig. 6) were also used to assist to justify that IBP and NIC would have
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actually formed a coamorphous system inside MSM instead of being present there as individual amorphous phases. When compared with the spectrum of physical mixture of amorphous IBP and amorphous NIC, namely the mixture of MSMs-loaded IBP and MSMs-loaded NIC, the spectrum of NCA system shows 0.4~0.5 ppm downfield shift of methyl resonances of IBP and 0.6 ppm upfield of
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carboxyl resonance. These changes in chemical shift can be attributed to the molecular interactions between IBP and NIC. Theoretically, the molecular interaction between drug and CF of a coamorphous
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system, although very weak, provides the only chance to distinguish the coamorpous state from the physical mixture of individual amorphous ingredients. 3.3 In vitro dissolution rate IBP drug loading in amorphous IBP system was determined as of 35.5±4.1% (w/w, n=3); while in NCA system, this percentage decreased to 16.7±2.7% (w/w, n=3) maybe because NIC occupied a part of pore volume. In vitro drug release experiments were performed under sink conditions. According to the dissolution
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showing the effect of nanoscale confinement in increasing drug dissolution rate. Under nanoscale confinement, pure IBP and the binary mixture of IBP-NIC have to exist in amorphous state because their particle sizes were limited
[6, 7]
. However, the granule size of crystalline IBP and its cocrystal
counterpart was still kept within the range of 10 to 50 µm even after comminution. Consequently, the
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rapid dissolution of NCA system was mainly attributed to its high dispersity and low crystallinity rather than the effect of NIC. And the high dispersity and low crystallinity obviously result from nanoscale
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confinement. 3.4 Kinetic solubility
Kinetic solubility studies were performed in distilled water. As can be seen from Fig. 8, IBP-NIC cocrystal and pure IBP reached their equilibrium solubility state 150 min after. However, it takes only 5
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min for the amorphous IBP and NCA systems to achieve that kind of state, which is in agreement with the dissolution profiles under sink condition. More importantly, NCA system showed the highest equilibrium solubility (154 µg/mL), nearly 2-fold higher than that of IBP drug substance.
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In NCA system, four factors codetermine the solubility of API: i) nanosized effect induced by the confinement of nanopores, which can increase the solubility according to Ostwald-Freundlich equation;
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ii) crystallization inhibition, which also has a positive impact on solubility; iii) decreased chemical potential due to the API-CF interaction, which can negatively affect solubility of API; iiii) hydrotropic effect of CF, which is not certainly exist in every API-CF system. So if the third factor is overwhelmed by other three factors, the solubility of API will be increased. The amorphous IBP also showed a higher solubility than IBP drug substance. When tested in pure water, the solubility of amorphous IBP did not reach the same value as NCA system until the same amount of NIC was added into the water medium, which confirmed the hydrotropic effect of NIC. Consequently, for this NCA system of IBP-NIC, the high solubility of IBP can be attributed to the hydrotropic effect of NIC as well as the confinement effect of nanopores.
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[10, 16]
. Here NCA system showed an
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equilibrium state of supersaturation instead of a “spring-parachute” shift through the whole course of experiment. It is not enough to attribute the disappearance of parachute merely to the precipitation inhibiting effect of NIC, because the amorphous IBP, in the absence of NIC, also showed no parachute. Then the only possible reason for the inhibition of recrystallization may be the lack of crystal nuclei.
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Theoretically, some methods to prepare amorphous drug (e.g. solvent evaporation and spray drying) are likely to induce a few number of crystals or nanocrystals whose content may be below the limit of
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detection of XRPD and DSC. Those crystals or nanocrystals, once formed, are certain to act as nuclei for precipitation or recrystallization, therefore the parachute comes out. However, it seems that the confinement effect of MSMs significantly reduced the number of nuclei in NCA system and amorphous IBP, hence the recrystallization is postponed. There is no doubt that the parachute of NCA system and amorphous IBP will eventually show up with time, however, the strategy of NCA, combining
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nanoscale confinement with coamorphous techniques, has clear advantages over the use of only the nanoscale confinement in increasing dissolution rate and solubility of the poorly water-soluble drug.
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4. Conclusion
Two strategies, nanoscale confinement and co-amorphism, were consolidated by loading a binary
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mixture of IBP and NIC into nanopores of MSMs. Coamorphous state of the so-called NCA system was confirmed by XRPD, DSC, FTIR and solid-state NMR results. Benefiting from both nanoscale confinement and CF, the NCA system performed better than its amorphous counterparts in apparent solubility and physical stability. Mesoporous silica appears to be a feasible tool to transform a cocrystal binary system into coamorphous solid. The NCA strategy can further increase the solubility, dissolution rate and physical stability of poorly water-soluble drugs, so it has great potential for oral, mucosal and transdermal drug delivery.
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Acknowledgments This work was supported by Shandong Provincial Natural Science Foundation, China (Nos. ZR2014HP020, ZR2014HL102 and ZR2014HL103), the National Natural Science Foundation of
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Taishan Medical University Foundation (No. 2014GCC04).
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China (No 81402899), Foundation of Shandong Provincial Education Department (J13LM01) and
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ACCEPTED MANUSCRIPT Fig. 1. SEM images of MSMs before (a) and after (b) the loading of 1:1 IBP-NIC.
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Scale bar: 30 µm.
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Fig. 2. XRPD patterns for crystalline IBP (a), physical mixture of crystalline IBP and
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NIC (mole ratio 1:1, b), IBP-NIC co-evaporated solid products with molar ratio of 2:1
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(c), 1:1 (d, cocrystal) and 1:2 (e). The highest peaks of IBP and NIC were respectively
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labeled using triangles and circles.
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Fig. 3. DSC curves of physical mixture of crystalline IBP and NIC (mole ratio 1:1, a),
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cocrystal IBP-NIC (b), amorphous IBP loaded in MSMs (C), amorphous NIC loaded
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in MSMs (d) and NCA system (e).
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Fig. 4. XRPD patterns for crystalline IBP (a), amorphous IBP (b) and NCA system (c).
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After 45 days storage at 60oC, the amorphous IBP (d) and NCA system (e) were
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measured again.
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Fig. 5. FTIR spectra for IBP (a), NIC (b), cocrystal IBP-NIC (c) and NCA system (d).
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Fig. 6. Solid-state
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amorphous IBP and amorphous NIC.
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Fig. 7. Dissolution profiles of amorphous IBP, NCA system, cocrystal system and IBP
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drug substance under sink condition.
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Fig. 8. Kinetic solubility curves of NCA system, cocrystal system, amorphous IBP
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and IBP drug substance in water and amorphous IBP in NIC solution (non-sink
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condition).
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S0022-3549(17)30442-2
DOI:
10.1016/j.xphs.2017.06.005
Reference:
XPHS 848
To appear in:
Journal of Pharmaceutical Sciences
Received Date: 27 March 2017 Revised Date:
23 May 2017
Accepted Date: 8 June 2017
Please cite this article as: Bi Y, Xiao D, Ren S, Bi S, Wang J, Li F, The binary system of ibuprofennicotinamide under nanoscale confinement: from cocrystal to coamorphous state, Journal of Pharmaceutical Sciences (2017), doi: 10.1016/j.xphs.2017.06.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The binary system of ibuprofen-nicotinamide under nanoscale confinement: from cocrystal to coamorphous state
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School of Pharmaceutical Sciences, Taishan Medical University, No. 619,
Changcheng Road, Tai’an, 271016, P.R. China
Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of
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Yanping Bi*,1, Deli Xiao 2, Shuai Ren 3, Shuyan Bi4, Jianzhu Wang1 , Fei Li1
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Education, China Pharmaceutical University, Nanjing, 210009, China
Graduate School, Taishan Medical University, No. 619, Changcheng Road, Tai’an,
271016, P.R. China. 4
Department of Ultrasound, Zibo Hospital of PKU Healthcare Industry Group , No.2,
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Xishanwu Street, Zibo, 255069, P.R. China. * Corresponding author. E-mail address: [email protected]; Tel/Fax:
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+8605386229751
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Abstract Coamorphous systems have gained success in stabilizing amorphous drugs and improving their solubility and dissolution. Here we proposed to confine a binary mixture of drug and coformer (CF) within nanopores to obtain a nano-confined coamorphous (NCA) system. For proving feasibility of this
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proposal, a poorly water-soluble drug (ibuprofen, IBP) and a frequently used pharmaceutical CF (nicotinamide, NIC) were loaded into nanopores of mesoporous silica microspheres (MSMs). The solid state of NCA system was characterized by differential scanning calorimetry, X-ray powder diffraction,
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infrared spectrum and solid state nuclear magnetic resonance. With large numbers of nanopores, MSMs appears to be a feasible carrier to transform a cocrystal system into co-amorphism by nanoscale
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confinement. Benefiting from both nanoscale confinement and CF, the NCA system of IBP achieved synchronic increase in dissolution properties and physical stability. Consequently, the NCA strategy is effective in achieving co-amorphous state and offers a promising alternative for formulating poorly water-soluble drugs.
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1. Introduction
Advanced drug discovery approaches often lead to the identification of poorly water-soluble drugs which face great challenges in formulating oral and transdermal dosage forms. In order to surmount the solubilization/dissolution bottleneck, several strategies, such as cocrystal, amorphous and coamorphous
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systems, have been applied to achieving the supersaturation state of drug solution [1, 2]. Pharmaceutical cocrystal is a structure in which an active pharmaceutical ingredient (API) and a neutral
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small-molecule coformer (CF) are incorporated within the same crystalline lattices in a specific stoichiometric amount. The CF can be another API but not a solvent molecule. Physicochemical properties of cocrystals of a given drug depend strongly on the structure of CF; so not every cocrystal form will deliver an improvement in dissolution properties relative to that of original API [3]. Amorphous drugs show a higher apparent solubility and dissolution rate than their crystalline counterparts due to the higher energetic state that does not require the crystal lattice to be broken upon dissolution. However, a pure amorphous API is thermodynamically unstable and prone to recrystallize during storage. The most commonly used strategy to suppress recrystallization of amorphous APIs is to
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[5]
[4]
. Recently, mesoporous silica has gained considerable success
. Once a drug is confined within rigid nanopores of the mesoporous
silica, the size of crystal nuclei will be limited. And if the nanopores are smaller than the critical nucleus size of the drug molecule, the nucleation will be inhibited, so the amorphous state is preserved .
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[6-8]
Besides, coamorphous strategy has also been used to stabilize amorphous drugs. As a special case of amorphous systems, coamorphous system is usually defined as the amorphous binary system of two drugs or a drug and a small molecule CF
[9]
. If the proper CF has been selected, evaporating the
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drug-CF solution will be enough to induce a coamorphous system because, to a certain extent, the CF itself can inhibit crystallization [10]. However, some modified methods, such as low-temperature milling and spray-drying
[12]
, are still absolutely necessary due to the fact that a direct evaporation
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[11]
procedure is more likely to result in a crystalline/co-crystalline system rather than a coamorphous system if the CF is not properly selected. Therefore, the CF selection work for a coamorphous system might be labor-intensive.
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Since confining a single drug in nanopores of mesoporous silica leads to amorphization, confining a cocrystal binary system (API&CF) in nanopores will possibily bring about a coamorphous system. For proving feasibility of this proposal, an acceptable pharmaceutical CF, also a frequently used water-soluble hydrotrope, namely nicotinamide (NIC), and a poorly water-soluble drug, namely
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ibuprofen (IBP), were synchronically loaded into mesoporous silica microspheres (MSMs). The obtained product differs from common bulk coamorphous system in its nanoscale confinement, which
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can be referred to as nano-confined coamorphous (NCA) system. The NCA system, together with amorphous IBP, IBP-NIC cocrystal and pure IBP drug substances, was investigated for its solid-state, dissolution rate and kinetic solubility.
2. Materials and methods 2.1 Materials Waterglass (WG, with a modulus of 3.3; Na2O, 8.3%; SiO2, 26.5%), Span-80, Tween-80 and NIC (99%) were purchased from Qingdao Usolf Chemtech Co.,Ltd (Qingdao, China). Ibuprofen (98%) was
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ACCEPTED MANUSCRIPT supplied by Wuhan Biocause Pharmaceutiacl Co., Ltd (Wuhan, China). Other Chemicals such as petroleum ether (boiling range 60~90oC), sucrose (analytical reagent), methanol (HPLC grade) and ammonium bicarbonate (NH4HCO3, analytical reagent) were purchased from Sinopharm Chemical Reagent Co., Ltd (Shanghai, China).
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2.2 Preparation of mesoporous silica microspheres The preparation of MSMs has been described in our previous report
[13]
. Here, 4g of WG was
dissolved in 6 g of sucrose solution (50%, w/w). Then 20 mL of petroleum ether solution of Span 80 (5%, w/v) was added into the WG solution with stirring for 1 min. Then the mixture was emulsified for
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2 min using a homogenizer (Heidolph DIAX 900) with 8000 rpm to obtain an emulsion (W/O). Finally, the emulsion was poured into 100 mL of an aqueous solution containing NH4HCO3 (15.8%, w/v) and
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Tween 80 (0.5%, w/v) and stirred for 1h for the formation of MSMs. The solid product was recovered, washed with distilled water and ethanol alternately, and air-dried at room temperature. 2.3 Preparation of co-evaporated solid products of IBP-NIC
IBP (2 mmol) and NIC in various molar ratios (2:1, 1:1 and 1:2) were dissolved in 5 mL ethanol at
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room temperature. The resulting clear solutions were allowed for evaporation in a crystallizing dish. After 24 h, solid products containing IBP-NIC of 2:1, 1:1 and 1:2 formed. 2.4 MSMs drug-loading procedure
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NCA system, amorphous IBP and amorphous NIC were prepared also by solvent evaporation method. Briefly, 1:1 mixture of IBP (2 mmol) and NIC (2 mmol) were dissolved in ethanol to obtain
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2.5 g of stock solution. Then 0.8 g of MSMs was suspended in the stock solution under supersonication. The suspension was centrifuged (4000 rpm, 1 min) and the supernatant was completely removed. Finally, the precipitate was dried at room temperature for 24 h to obtain NCA system. By the same procedure, MSMs were respectively immersed into IBP solution and NIC solution to obtain amorphous IBP and amorphous NIC. 2.5 Characterization of drug delivery systems The morphology of NCA system and blank MSMs were studied by a scanning electron microscope (SEM, Quanta 200 FEG, FEI Co., USA) at an acceleration voltage of 20 kV without any coating
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outgassed under high vacuum for 15 min at room temperature. The specific surface area was determined according to the BET method, and the pore size distribution was determined from adsorption branch of isotherm using the Barrett-Joyner-Halenda (BJH) method. The total pore volume
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was determined from the amount adsorbed at a relative pressure of 0.99.
The X-ray powder diffraction (XRPD) patterns were recorded on a D8 Advance X-Ray
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Diffractometer (Bruker-AXS, USA) using CuKα monochromatized radiation at 40 kV, 40 mA. The step scan mode was performed with a step size of 0.02° at a rate of 2°/min.
The thermal properties of powders were studied using a TA Instruments Q-2000 differential scanning calorimetry (DSC). The system was calibrated using indium and an empty pan was used as reference. Typically, 5 mg samples were placed on non-hermetic aluminium pans. Samples were analyzed at a
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heating rate of 10 ºC/min from 30 to 150 ºC under a constant flow of nitrogen. An IRAffinity-1S Fourier Transform Infrared (FT-IR) Spectrophotometer (Shimadzu Corporation, Kyoto, Japan) was employed for recording the IR spectra of samples. Typically, 4 mg of each sample
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was mixed with 100 mg KBr, compressed into tablets and scanned from 400 cm−1 to 4000 cm−1 with a spectral resolution of 4 cm−1. 13
C nuclear magnetic resonance (NMR) experiments were performed using Bruker
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Solid-state
Avance 400 at Larmor frequencies of 400 MHz at 298K. The CP/MAS experiments were carried out using a double-tuned CP/MAS probe equipped for 4 mm outer diameter rotors, a spin rate of 12.5 kHz, 4096 scans. The spectra were referenced to an external sample of methylene carbon of adamantane at 38.48 ppm. 2.6 Drug loading efficiency Drug loading efficiency was determined by adding 50 mg of NCA or amorphous IBP in 250 ml ethanol with stirring for 2 h. Then 5 mL of the supernatant was filtered through a 0.22-µm nylon
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(w/v) aqueous phosphoric acid-methanol (20:80) at the detection wavelength of 220 nm. The flow rate was 1.0 ml/min at room temperature. Ethanol solutions of IBP were used as standard solutions to draw the standard curve. In the concentration range of 1.52~381 µg/ml, the concentration of IBP (Y) correlated well to its peak area (X): Y= 0.00003237X-0.4448 (r = 0.9998, n = 3).
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2.7 Dissolution rate
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Dissolution profiles of the four samples, 30 mg of IBP, 48 mg of cocrystal, 85 mg of amorphous IBP and 170 mg of NCA system, were tested using a dissolution testing instrument (ZRS-8G, Tianda Tianfa Technology Co., Ltd., Tianjin, China). In each test, 500 mL of aqueous solution of Tween 80 (0.1%, w/v) was first placed in the vessel and allowed to come to 37°C before the sample was added. The paddle rotational speed was 100 rpm. At each predetermined time (5, 15, 30, 45, 60, 90, 120 150, 180,
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240 and 400 min), a 5 ml sample was withdrawn and passed through a 0.22-µm syringe filter. Then the IBP concentration was determined by HPLC-UV method (2.6).
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2.8 Kinetic solubility
For kinetic solubility studies of the systems, the equivalent of 50 mg IBP was used employing a
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magnetic stirring speed of 100 rpm and the temperature was maintained at 37 ºC. The dissolution medium was 100 mL of distilled water. As a comparison, amorphous IBP was also tested in an aqueous solution containing 29.6 mg of NIC (because the NCA system used here also contains 50 mg of IBP and 29.6 mg of NIC). Sampling was performed at 5, 10, 20, 30, 60, 90, 120, 150, 180, 210 and 240 min and the withdrawn suspension was filtered through a 0.22-µm syringe filter. The first 4 mL of filtrate was discarded and subsequent filtrate was collected. Then 500 µL of the subsequent filtrate was pipetted accurately into a 1.5 ml centrifuge tube and diluted with equivoluminal aqueous solution of Tween 80 (0.2%, w/v). Then the drug concentration was determined by HPLC-UV method (2.6).
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3. Results and Discussion 3.1 Characterization of MSMs The SEM image of MSMs (Fig. 1a) reveals a spherical morphology with a size ranged from 5 to 15 µm in diameter. Type IV isotherm (Fig. S1, Supporting Information), as well as the SEM image,
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indicates the presence of large amounts of mesopores in MSMs. An average pore diameter of 16.1 nm (Fig. S2a, Supporting Information) and a total pore volume of 1.67 cm3/g imply the potential of MSMs as drug carrier for delivery of both small and large molecule drugs. The large specific surface area (590
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m2/g) paves the way for rapid drug dissolution. After the loading of 1:1 IBP-NIC, the nanopores of MSMs were partially filled and became invisible in SEM image (Fig. 1b), correspondingly, the specific
5.19 nm (Fig. S2b) and 0.61 cm3/g.
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surface area, the average pore diameter and the total pore volume respectively decreased to 407 m2/g,
3.2 Characterization of drug delivery systems
Fig. 2 presents the XRPD patterns of co-evaporated solid products of IBP-NIC. The 1:1 co-evaporated product shows different characteristic peaks from the drug and CF (Fig. 2d), so its
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cocrystal state can be confirmed, plus the single melting peak at 94.6oC in DSC curve (Fig.3b). However, the patterns of 2:1 co-evaporated product shows the representative peaks of IBP (Fig. 2c), indicating the individual phase of remaining IBP. Similarly, the 1:2 co-evaporated product presents
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some remaining NIC (Fig. 2e).
After being loaded into nanopores of MSMs, the binary mixture of 1:1 IBP-NIC and the pure IBP
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show neither typical melting point in DSC curve (Fig. 3c, e) nor diffraction peaks in XRPD pattern (Fig. 4b, c), which indicates their amorphous state. The formation of amorphous/coamorphous type results from the nanoscale confinement rather than the addition of NIC, so the MSMs-loaded binary system of 1:1 IBP-NIC can be referred to as NCA system. Microscope image of the NCA system did not show any crystalline solid outside MSMs (Fig. 1), so we can conclude that IBP and NIC were deposited in nanopores. After 45 days of storage at 60oC, small crystalline peaks might be observed on the amorphous IBP pattern (Fig. 4d) while the NCA system remained unchanged (Fig. 4e), proving that incorporating a
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cm-1 and 3182 cm-1, respectively; the C=O stretching peak of IBP also shifted from 1721 cm-1 to 1707 cm-1. Those two variations indicate the hydrogen bond between the carboxyl group of IBP and the acylamino group of NIC in cocrystal system. The two peaks at 1506 cm-1(IBP) and 1485 cm-1(NIC), representing the skeleton vibrations of the aromatic rings, merged into single one (1516 cm-1) in
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cocrystal system, which demonstrated the π-π interaction between IBP and NIC molecule. Obviously, the NCA system exhibits the same spectrum characteristics with cocrystal system. The similarity
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between IR spectra of NCA system and that of cocrystal system provides an indirect proof that IBP-NIC interaction also exists in NCA system, hence confirms the homogeneity at molecular level and the coamorphous state of NCA system.
Solid-state 13C NMR spectra (Fig. 6) were also used to assist to justify that IBP and NIC would have
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actually formed a coamorphous system inside MSM instead of being present there as individual amorphous phases. When compared with the spectrum of physical mixture of amorphous IBP and amorphous NIC, namely the mixture of MSMs-loaded IBP and MSMs-loaded NIC, the spectrum of NCA system shows 0.4~0.5 ppm downfield shift of methyl resonances of IBP and 0.6 ppm upfield of
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carboxyl resonance. These changes in chemical shift can be attributed to the molecular interactions between IBP and NIC. Theoretically, the molecular interaction between drug and CF of a coamorphous
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system, although very weak, provides the only chance to distinguish the coamorpous state from the physical mixture of individual amorphous ingredients. 3.3 In vitro dissolution rate IBP drug loading in amorphous IBP system was determined as of 35.5±4.1% (w/w, n=3); while in NCA system, this percentage decreased to 16.7±2.7% (w/w, n=3) maybe because NIC occupied a part of pore volume. In vitro drug release experiments were performed under sink conditions. According to the dissolution
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showing the effect of nanoscale confinement in increasing drug dissolution rate. Under nanoscale confinement, pure IBP and the binary mixture of IBP-NIC have to exist in amorphous state because their particle sizes were limited
[6, 7]
. However, the granule size of crystalline IBP and its cocrystal
counterpart was still kept within the range of 10 to 50 µm even after comminution. Consequently, the
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rapid dissolution of NCA system was mainly attributed to its high dispersity and low crystallinity rather than the effect of NIC. And the high dispersity and low crystallinity obviously result from nanoscale
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confinement. 3.4 Kinetic solubility
Kinetic solubility studies were performed in distilled water. As can be seen from Fig. 8, IBP-NIC cocrystal and pure IBP reached their equilibrium solubility state 150 min after. However, it takes only 5
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min for the amorphous IBP and NCA systems to achieve that kind of state, which is in agreement with the dissolution profiles under sink condition. More importantly, NCA system showed the highest equilibrium solubility (154 µg/mL), nearly 2-fold higher than that of IBP drug substance.
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In NCA system, four factors codetermine the solubility of API: i) nanosized effect induced by the confinement of nanopores, which can increase the solubility according to Ostwald-Freundlich equation;
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ii) crystallization inhibition, which also has a positive impact on solubility; iii) decreased chemical potential due to the API-CF interaction, which can negatively affect solubility of API; iiii) hydrotropic effect of CF, which is not certainly exist in every API-CF system. So if the third factor is overwhelmed by other three factors, the solubility of API will be increased. The amorphous IBP also showed a higher solubility than IBP drug substance. When tested in pure water, the solubility of amorphous IBP did not reach the same value as NCA system until the same amount of NIC was added into the water medium, which confirmed the hydrotropic effect of NIC. Consequently, for this NCA system of IBP-NIC, the high solubility of IBP can be attributed to the hydrotropic effect of NIC as well as the confinement effect of nanopores.
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[10, 16]
. Here NCA system showed an
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equilibrium state of supersaturation instead of a “spring-parachute” shift through the whole course of experiment. It is not enough to attribute the disappearance of parachute merely to the precipitation inhibiting effect of NIC, because the amorphous IBP, in the absence of NIC, also showed no parachute. Then the only possible reason for the inhibition of recrystallization may be the lack of crystal nuclei.
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Theoretically, some methods to prepare amorphous drug (e.g. solvent evaporation and spray drying) are likely to induce a few number of crystals or nanocrystals whose content may be below the limit of
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detection of XRPD and DSC. Those crystals or nanocrystals, once formed, are certain to act as nuclei for precipitation or recrystallization, therefore the parachute comes out. However, it seems that the confinement effect of MSMs significantly reduced the number of nuclei in NCA system and amorphous IBP, hence the recrystallization is postponed. There is no doubt that the parachute of NCA system and amorphous IBP will eventually show up with time, however, the strategy of NCA, combining
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nanoscale confinement with coamorphous techniques, has clear advantages over the use of only the nanoscale confinement in increasing dissolution rate and solubility of the poorly water-soluble drug.
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4. Conclusion
Two strategies, nanoscale confinement and co-amorphism, were consolidated by loading a binary
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mixture of IBP and NIC into nanopores of MSMs. Coamorphous state of the so-called NCA system was confirmed by XRPD, DSC, FTIR and solid-state NMR results. Benefiting from both nanoscale confinement and CF, the NCA system performed better than its amorphous counterparts in apparent solubility and physical stability. Mesoporous silica appears to be a feasible tool to transform a cocrystal binary system into coamorphous solid. The NCA strategy can further increase the solubility, dissolution rate and physical stability of poorly water-soluble drugs, so it has great potential for oral, mucosal and transdermal drug delivery.
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Acknowledgments This work was supported by Shandong Provincial Natural Science Foundation, China (Nos. ZR2014HP020, ZR2014HL102 and ZR2014HL103), the National Natural Science Foundation of
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Taishan Medical University Foundation (No. 2014GCC04).
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China (No 81402899), Foundation of Shandong Provincial Education Department (J13LM01) and
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Scale bar: 30 µm.
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Fig. 2. XRPD patterns for crystalline IBP (a), physical mixture of crystalline IBP and
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NIC (mole ratio 1:1, b), IBP-NIC co-evaporated solid products with molar ratio of 2:1
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(c), 1:1 (d, cocrystal) and 1:2 (e). The highest peaks of IBP and NIC were respectively
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labeled using triangles and circles.
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Fig. 3. DSC curves of physical mixture of crystalline IBP and NIC (mole ratio 1:1, a),
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cocrystal IBP-NIC (b), amorphous IBP loaded in MSMs (C), amorphous NIC loaded
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in MSMs (d) and NCA system (e).
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Fig. 4. XRPD patterns for crystalline IBP (a), amorphous IBP (b) and NCA system (c).
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After 45 days storage at 60oC, the amorphous IBP (d) and NCA system (e) were
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measured again.
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Fig. 5. FTIR spectra for IBP (a), NIC (b), cocrystal IBP-NIC (c) and NCA system (d).
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Fig. 6. Solid-state
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amorphous IBP and amorphous NIC.
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Fig. 7. Dissolution profiles of amorphous IBP, NCA system, cocrystal system and IBP
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drug substance under sink condition.
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Fig. 8. Kinetic solubility curves of NCA system, cocrystal system, amorphous IBP
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and IBP drug substance in water and amorphous IBP in NIC solution (non-sink
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condition).
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C NMR spectra of NCA system (a) and the physical mixture of
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