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Jul 23, 2018 - and Changquan Calvin Sun*,†. †. Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College o...
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Preparation, characterization, and formulation development of drugdrug protic ionic liquids of diphenhydramine with ibuprofen and naproxen Chenguang Wang, Sujay A. Chopade, Yiwang Guo, Julia T. Early, Boxin Tang, En Wang, Marc A. Hillmyer, Timothy P. Lodge, and Changquan Calvin Sun Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00569 • Publication Date (Web): 23 Jul 2018 Downloaded from http://pubs.acs.org on July 23, 2018

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Molecular Pharmaceutics

Preparation, characterization, and formulation development of drug-drug protic ionic liquids of diphenhydramine with ibuprofen and naproxen

Chenguang Wang,†,# Sujay A. Chopade,‡,# Yiwang Guo,† Julia T. Early,§ Boxin Tang,‡ En Wang,‡ Marc A. Hillmyer,§ Timothy P. Lodge,‡,§ and Changquan Calvin Sun†,*



Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics,

College of Pharmacy; ‡Department of Chemical Engineering and Materials Science, and §

Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455-0431,

United States

# C.W. and S.A.C. contributed equally.

*Corresponding author Changquan Calvin Sun, Ph.D. 9-127B Weaver-Densford Hall 308 Harvard Street S.E. Minneapolis, MN 55455 Email: [email protected] Tel: 612-624-3722 Fax: 612-626-2125

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ABSTRACT

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Diphenhydramine (DPH) has been used with ibuprofen (IBU) or naproxen (NAP) in combined

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therapies to provide better clinical efficacy as an analgesic and sleep aid. We discovered that

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DPH can form protic ionic liquids (PILs) with IBU and NAP, which opens the opportunity for a

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new delivery mode of these combination drugs. [DPH][IBU] and [DPH][NAP] PILs exhibit low

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ionicity, as confirmed by FT-IR and 1H NMR spectroscopy, and accompanied by low diffusivity,

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high viscosity, and poor ionic conductivity. Evaluation of pharmaceutical properties of the two

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PILs showed that these PILs, despite high solubility and good wettability, exhibited low

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dissolution rates, owing to the poor dispersion of the PIL drops and the resultant small surface

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area during dissolution. However, when loaded into a mesoporous carrier, the PIL-carrier

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composites exhibited improved dissolution rates along with excellent flow properties and easy

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handling. Oral capsules of both PILs were developed using such composites. Such capsule

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products exhibited acceptable drug release and bioavailability as demonstrated by a predictive

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artificial stomach‐duodenum dissolution test.

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KEYWORDS: ionic liquids, drug combinations, active pharmaceutical ingredients, ionicity,

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dissolution, particle engineering

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Molecular Pharmaceutics

INTRODUCTION

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The use of synergistic drug combinations has become popular due to the improvement in

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compliance, safety, and effectiveness.1-3 Examples of drug-drug combinations with commercial

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success include sulfamethoxazole/trimethoprim (Bactrim), carbidopa/levodopa (Sinemet),

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fluticasone/salmeterol (Advair Diskus), isoniazid/rifampicin (IsonaRif), niacin/lovastatin

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(Advicor), zidovudine/lamivudine (Combivir),4 and valsartan/sacubitril (Entresto).5 The recently

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approved valsartan/sacubitril combination is more effective than the current first-line drug of

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enalapril in reducing the risk of death from cardiovascular causes or hospitalization for heart

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failure.6 The potential clinical benefits and the increasing level of difficulty in developing a new

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chemical entity have attracted interest in developing drug-drug combinations.7

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Diphenhydramine (DPH, Scheme 1) is a first-generation H1-receptor antagonist and is

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used as a sedative, hypnotic, antihistamine, and antiemetic agent.8 Combinations of DPH with

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the non-steroidal anti-inflammatory drugs ibuprofen (IBU) or naproxen (NAP) (Scheme 1) are

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commercialized as Advil PM® and Aleve PM®, respectively. They exhibit superior analgesic

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efficacy and provide better nighttime sleep quality over their individual dosage forms. The

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bilayer tablet is used to deliver these drug combinations. However, manufacturing bilayer tablets

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requires a specialized tableting press and tends to face more manufacturing problems than single

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layer tablets,9 such as layer splitting.10

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New combination drugs could be assembled through crystal engineering, such as salt and

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co-crystal formation, where two drug molecules are linked together through reversible

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intermolecular interactions without changing their pharmacological profiles.11 Successful

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examples include Entresto, a co-crystal hydrate between sacubitril sodium and valsartan, and a

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salt co-crystal between tramadol hydrochloride and celecoxib.12-14 During the effort to prepare

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new crystal forms of DPH with IBU and NAP, where ∆pKa between the protonated DPH and

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IBU is 3.9 and that between protonated DPH and NAP is 4.4, we found that the two drug

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combinations formed liquids at room temperature. 3 ACS Paragon Plus Environment

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ILs are salts with low melting points (below 100 °C), comprised mostly of organic ions.

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ILs have attracted considerable attention by virtue of their appealing physical characteristics,

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such as non-volatility and high thermal, chemical, and electrochemical stability.15 They also have

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broader applicability due to their favorable ionic conductivity and attractive physical properties

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as solvents for electrochemical processes, their crucial role in various emerging technologies,

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including fuel cells, batteries, and bio-catalysts, as well as delivery of pharmaceutical actives.16-24

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In contrast to common solid forms, pharmaceutical ILs offer another effective approach to

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modifying the drug physicochemical and biopharmaceutical properties, including solubility,

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dissolution rate, permeability, stability, and bioavailability.25-30 One advantage of ILs is the

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absence of the polymorphism issue.31 The protic IL (PIL) is a subclass of IL that is formed

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between Brönsted acid (AH) and Brönsted base (B) through proton transfer.21, 32 Neutral acid and

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base species could be observed in PILs, where ionicity depends on degree of complete of proton

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transfer during the equilibrium shown in eq. 1.33-35

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AH + B ⇌ A − H ··· B ⇌ BH + A

(1)

The degrees of ionicity can significantly affect viscosity, conductivity, and permeability.

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PILs with low ionicity are sometimes termed poor ionic liquids,32 or deep eutectic liquid co-

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crystals.36, 37 They are different from deep eutectic solvents.36, 38

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In this study, PILs of DPH with two common drugs, NAP and IBU, were synthesized and

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characterized. Their solubility and dissolution were systematically assessed. Although ILs have

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many potential advantages, they can be difficult to handle during pharmaceutical manufacturing.

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To enable the development of PILs based oral solid product, a mesoporous carrier was used as a

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delivery vehicle to render good processability. Thus, this work exemplifies the study of

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pharmaceutical PILs, from PIL synthesis and characterization to the development of oral solid

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formulations exhibiting desired dissolution properties. We note that the 1:1 stoichiometry of

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both PILs between two drugs differs from the relative ratios in commercial Advil® PM or Aleve®

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PM combo formulations. Thus, this work demonstrates the possible advantages of such PILs and 4 ACS Paragon Plus Environment

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Molecular Pharmaceutics

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their pharmaceutical development but does not suggest direct replacement of their commercial

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combo tablet products.

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Scheme 1. Molecular structure of diphenhydramine (MW = 255 g/mol), (±) ibuprofen (MW = 206 g/mol), and (-) naproxen (MW = 230 g/mol).

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EXPERIMENTAL SECTION

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Materials

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Diphenhydramine hydrochloride ([DPH][HCl]), racemic sodium ibuprofen ([Na][IBU]),

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and (S)-naproxen were purchased from Sigma Aldrich (St. Louis, MO). (S)-Naproxen sodium

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([Na][NAP]) was purchased from Spectrum Chemical Mfg. Corp (New Brunswick, NJ), a

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mesoporous silica, Aeroperl® 300 Pharma, was donated by Evonik Inc. (Essen, Germany), and

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racemic ibuprofen was donated by BASF Chemical Co. (Ludwigshafen, Germany).

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Diphenhydramine free base was prepared by neutralizing [DPH][HCl] with sodium hydroxide

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solution and then extracted by ethyl acetate. All other materials were used as received.

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Synthesis of PILs

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PILs were prepared via a metathesis reaction between [DPH][HCl] and [Na][IBU] or

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[Na][NAP].39,

40

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methanol. To this stirred solution, 50 mL of [DPH][HCl] methanol solution (0.2 M) was slowly

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added (Scheme 2). The reaction mixture was heated to 40 °C and stirred vigorously for 48 h.

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Methanol was then removed using a rotary evaporator, and 100 mL of dichloromethane was

In a round bottom flask, [Na][IBU] (10 mmol) was dissolved in 50 mL

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added to the reaction mixture. The mixture was washed 3 times with deionized water to remove

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NaCl. After separation, magnesium sulfate was placed in the organic phase and vigorously

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shaken to remove water. The solvent in the filtered solution was removed using a rotary

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evaporator (ca. 100 mTorr) at 35 °C. Subsequently, the [DPH][IBU] PIL was dried at 50 °C

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under vacuum (ca. 10 mTorr) for 24 h. A similar method was followed to prepare [DPH][NAP]

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PIL using [Na][NAP] and [DPH][Cl] (Scheme 2), except deionized water was used to replace

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methanol in the metathesis reaction.

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Scheme 2. Synthesis of [DPH][NAP] and [DPH][IBU] PILs from their respective commercial salts via metathesis reactions.

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Formulation of PILs

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Each PIL was dissolved in methanol to obtain a 0.2 g/mL solution. The solution was

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added to the mesoporous silica powder at 1:1 ratio (v/w). The wet powder was dried at 40 °C in a

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vacuum oven for 48 h to remove the methanol. The dried powders contained ~20% (w/w) PILs.

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Vibrational Spectroscopy

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A confocal Raman microscope (Alpha300 R, WITec, Ulm, Germany) was used to

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acquire the spectra of the PILs and raw materials. The laser source was set at 532 nm with an

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integration time of 10 s. The average spectrum of two accumulations was obtained for each

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sample. IR spectra of PILs were collected using a spectrometer (Nicolet iS50, Thermo Scientific,

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Waltham, MA) with a built-in diamond attenuated total reflection with DLaTGS detector. For 6 ACS Paragon Plus Environment

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Molecular Pharmaceutics

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each sample, 32 scans were averaged. IR data in the range of 4000–450 cm–1 at a resolution of 2

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cm–1 were processed using the software OMNIC 9.2.

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Mass Spectrometry (ESI-MS) and Elemental Analysis

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Accurate mass measurements of PILs were acquired by direct infusion electrospray

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ionization mass spectrometry on a mass spectrometer (BioTOF II, Bruker, Billerica, MA). Both

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samples were dissolved in methanol. The cations were analyzed in positive ion mode and the

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anions in negative ion mode. The elemental analyses of the PILs were performed on a CHN

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analyzer (Perkin Elmer 2400, Waltham, MA).

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Pulsed-Field-Gradient 1H NMR Spectroscopy (PFG-NMR)

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1

H and PFG-NMR spectroscopy were performed using a 500 MHz NMR spectrometer

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(Avance III, Bruker, Billerica, MA) equipped with a 5-mm triple resonance broad band pulsed-

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field gradient probe. The PIL sample was placed in the outer tube of a coaxial NMR tube setup

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with d6-dimethyl sulfoxide (DMSO) filled in the inset tube.41 All PFG-NMR experiments were

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performed for 1H nuclei with DOSY using the longitudinal eddy current delay experiment using

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bipolar gradients acquired in 2D mode pulse sequence.42 Self-diffusion coefficients of the PIL

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constituent species were determined in the temperature range of 27–71 °C. At each temperature,

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the PIL sample was equilibrated for at least 30 min before conducting the NMR experiment. The

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translational diffusion coefficients were obtained by using eq. 2: (2)

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where I/I0 is the attenuated intensity (I) at various gradient strengths (G) from 2 to 98% of the

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maximum G (0.47 T/m) normalized to I0 at G = 0, and γ is the 1H gyromagnetic ratio (42.6

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MHz/T). Signal attenuation was detected using a diffusion time (∆) of 0.7 s and a gradient pulse

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time (δ) of 3 ms for [DPH][IBU]; for [DPH][NAP] ∆ was 0.8 s, and δ was 3 ms. The PFG-NMR

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results were processed using Top Spin 3.5vl7 software package.

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Thermal Analysis 7 ACS Paragon Plus Environment

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Thermal properties of PILs were characterized by differential scanning calorimetry

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(DSC) using a Discovery Calorimeter (TA Instruments, New Castle, DE). Samples were packed

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into aluminum T-zero pans and hermetically sealed with aluminum lids, and subjected to three

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cycles of cooling and heating at 10 °C/min over the temperature range from –90 °C to 90 °C. The

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cell was purged with dry nitrogen at 50 mL/min. Thermogravimetric analysis (TGA) of the PIL

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samples was performed on a thermogravimetric analyzer (Q500, TA Instruments, New Castle,

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DE) under 60 mL/min N2 at a heating rate of 10 °C/min from room temperature to 450 °C.

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Viscosity Measurements

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Rheological measurements were carried out on a rheometer (AR-G2, TA Instruments,

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New Castle, DE) with Peltier temperature control, using the 25 mm parallel plate geometry.

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Steady shear rate sweep experiments were conducted over the range from 1 to 100 s–1 at

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temperatures from 25 ºC to 65 ºC in 10 ºC intervals, while maintaining a constant plate-to-plate

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gap (≈ 0.8 mm) by taking into account thermal expansion of the tools.

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Impedance Spectroscopy

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Ionic conductivity of the PILs was measured by 2-point probe AC impedance

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spectroscopy using a frequency response analyzer (Solartron 1255B, West Sussex, UK) and an

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electrochemical interface (SI 1287). The viscous PIL sample was contained in a Teflon spacer

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sandwiched between two stainless steel blocking electrodes in a home-built sealed conducting

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cell.43 The conductivity measurements were performed over the temperature range from 25 to 65

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°C by applying an alternating voltage signal of 100 mV in the frequency range of 1 – 106 Hz.

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The ionic conductivity, σ, was calculated as l/(RA), where l and A are the sample thickness and

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superficial area of the sample (determined by the geometry of the Teflon spacer) and R is the

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bulk resistance. Bulk resistance was determined from the minimum in the Nyquist plot (higher x-

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intercept of the semi-circle) of the negative imaginary component of the impedance, Z′′, versus

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the real component of the impedance, Z′. A set of representative raw impedance data is shown in

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Figure S1. 8 ACS Paragon Plus Environment

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Molecular Pharmaceutics

Contact Angle Measurement

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Contact angles were measured using the sessile drop method on a goniometer (DM-CE1,

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Kyowa Interface Science, Saitama, Japan). A drop of the PIL was sandwiched between two clean

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glass slides in orthogonal direction. One slide was moved along the long axis of another glass

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slide to produce a flat liquid film. The contact angle of the liquid film was recorded as a function

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of time. A drop of distilled water (∼3 µL) was placed on the surface of the films using a fine

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needle attached to a dispenser. The shape of the water drop was recorded every 1 s for 30 s using

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a high-speed camera. The angle between the sample surface and the tangent line at the edge of

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the drop was determined using image analysis software, FAMAS3.72 (Kyowa Interface Science

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Co. Ltd., Japan). Six measurements were made at different locations on each film, and the mean

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and standard deviations were calculated.

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Dynamic Water Vapor Sorption Isotherm

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Water sorption isotherms of the materials were obtained using an automated vapor

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sorption analyzer (Intrinsic DVS, Surface Measurement Systems Ltd., Allentown, PA) at 25 °C.

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The nitrogen flow rate was 50 mL/min. Each sample was first purged with dry nitrogen until a

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constant weight was obtained. Then, the sample was exposed to a series of relative humidities

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(RH) from 0% to 95% with the step size of 5% RH. At each specific RH, the equilibration

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criterion of either dm/dt ≤ 0.002% with a minimum equilibration time of 0.5 h or a maximum

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equilibration time of 6 h was applied. The RH was changed to the next target value once one of

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the criteria was met.

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Powder X-ray Diffraction

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Formulations of PILs were characterized using a powder X-ray diffractometer

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(PANalytical X'pert pro, Westborough, MA) with Cu Kα radiation. PXRD patterns were

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obtained by scanning samples from 5° to 35° with a step size of 0.017° and 2 s dwell time at

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room temperature. The tube voltage and amperage were set at 40 kV and 40 mA, respectively.

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Powder Flowability 9 ACS Paragon Plus Environment

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Powder flow properties of PILs formulation were characterized using a ring shear tester

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(RST-XS, Dietmar Schulze, Wolfenbüttel, Germany). A 30 mL volume shear cell was used to

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measure the flowability at 1 kPa preshear normal stress. Shear strength was determined under

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five progressively increasing normal stresses of 230, 400, 550, 700, and 850 Pa and used to

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construct a yield locus, from which the unconfined yield strength and major principal stress were

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obtained and powder flowability index (ffc) was calculated. The test was repeated three times

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using fresh samples.

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Thermodynamic Solubility

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The solubilities of the PILs, IBU, and NAP free acids were determined by equilibrating

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excess amount of each sample (200 mg) in ~5 mL of water or a pH 6.8 phosphate buffer at 25 °C

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under vigorous stirring for more than 72 h. The suspensions were filtered using 0.45 µm

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membrane filters. The concentration of filtrates was determined by UV spectroscopy (Ocean

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Optics, Inc., Dunedin, FL) after appropriate dilution.

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Single vessel Dissolution Test

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Dissolution rates were determined in 250 mL sodium phosphate buffer (pH = 6.8) at 37

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°C. The medium was stirred with an overhead stirrer at 80 rpm. As prepared PIL or its

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formulation was filled into a clear capsule shell (size 2) and placed in the dissolution medium.

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For [DPH][NAP], absorption spectra are sufficient different to allow monitoring the release of

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individual drug substance from these capsules using a fiber optic probe for UV spectroscopy

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(Ocean Optics, Inc., Dunedin, FL). The original drug concentration UV absorption spectrum,

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over the wavelength range from 200–400 nm, was processed by Oceanview 1.5.0 (Ocean Optics,

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Inc., Dunedin, FL). Since the UV absorption spectra of DPH and IBU are almost superimposable

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(Figure S2), their dissolution profiles could not be individually measured. Therefore, the sum of

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their concentrations was determined based on absorption signal using a calibration curve (Figure

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S3) to get a dissolution profile of both DPH and IBU.

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Artificial Stomach-Duodenum Dissolution (ASD) 10 ACS Paragon Plus Environment

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Molecular Pharmaceutics

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Dissolution of [DPH][NAP] was also determined using an artificial stomach-duodenum

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(ASD) apparatus, which consists of two jacketed beakers with temperature control at 37 °C using

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a water bath (Scheme 2). This apparatus simulates stomach and duodenum, where the fluid flow

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is regulated by a programmatically controlled peristaltic Masterflex L/S Easy-Load II pump

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(Cole-Parmer, Vernon Hills, IL).44-46

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To simulate human physiological conditions in the fasted state, experiments were

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conducted with 0.01 N HCl (pH = 2) for the stomach and 0.1 M sodium phosphate buffer (pH =

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6.8) for the duodenum. The initial volume of the stomach chamber was 250 mL, which was

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decreased to 50 mL by first-order emptying with a half-life of 15 min. The duodenum volume

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was maintained at 30 mL throughout the entire study, achieved by setting a vacuum line in the

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duodenum chamber at a calibrated height. In addition, the chambers were infused with fresh

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gastric or duodenal secretion liquid at 2 mL/min to mimic in vivo secretion processes. Drug

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concentration was determined from second derivatives of absorbance signals obtained by a fiber

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optic UV/Vis probe. Mixing was achieved by an overhead paddle stirrer in the stomach chamber

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and a magnetic stirrer in the duodenum chamber. Prior to each experiment, calibration of all

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pumps and spectrometers were performed. PILs and their formulations were filled into capsules.

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All fluids used in the experiment were degassed to avoid the introduction of bubbles that might

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affect the real-time UV detection.

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The drug concentration-time profile in the duodenum was analyzed by PKsolver 2.0, and

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the non-compartmental method was used to calculate the peak plasma concentration (Cmax), time

230

to reach Cmax (Tmax), and area under the plasma concentration-time curve (AUC).47

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Scheme 3. Schematic diagram of the artificial stomach-duodenum apparatus.

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RESULTS AND DISCUSSION

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Structural characterization of the PILs

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The synthesized [DPH][IBU] and [DPH][NAP] PILs were clear, viscous liquids at room

238

temperature (Figure S4), whereas [DPH][Cl], [Na][IBU] dihydrate, and[Na][NAP] hydrate were

239

white powders. Characteristic peaks of both reactants were observed in the FT-IR and Raman

240

spectra of both PILs (Figure 1), which suggest the presence of [DPH] and the corresponding free

241

acids. (a)

(b)

242 243 244 245

Figure 1. a) FT-IR and b) Raman spectra of [DPH][IBU] and [DPH][NAP] PILs and their corresponding starting materials.

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Molecular Pharmaceutics

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The purity of the PILs was confirmed by NMR spectroscopy, mass spectrometry, and

247

elemental analysis. The detailed 1H, 13C NMR spectroscopy results are provided in Figure S5. A

248

silver nitrate test was also performed to confirm the absence of chloride ions in the final

249

products.

250

The most significant change in 1H NMR spectra after formation of [DPH][NAP] and

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[DPH][IBU] is in the chemical shifts of the methine and methyl protons alpha to the carboxylate

252

(∆δ = 0.1 – 0.4 ppm). In general, the 1H chemical shifts for both anions shifted downfield. The

253

opposite trend was observed for the cations, as the 1H chemical shifts generally shifted upfield

254

with respect to the hydrochloride salt precursors. For the [DPH], the methyl and methine protons

255

adjacent to the amine exhibited significant upfield shifts (∆δ = 0.6 – 0.8 ppm). The carboxylic

256

acid proton is observed in both [DPH][NAP] and [DPH][IBU] at 9.66 ppm and 11.76 ppm,

257

respectively. The chemical shift of this proton in the [DPH][Cl] precursor is 10.67 ppm.

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The ESI-MS spectra of [DPH][IBU] and [DPH][NAP] were obtained in both positive and

259

negative modes to analyze both the anion and cation structures. In positive mode, the molecular

260

ion with m/z 256.2 corresponds with the [DPH]+ cation for both PILs. In negative mode, the

261

[NAP]– anion has an m/z of 229.1, whereas the m/z of 205.1 corresponds with the [IBU]– anion.

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Elemental analyses of the [DPH][IBU] and [DPH][NAP] PILs yielded results close to those

263

calculated from molecular formulas (Table S1).

264

Thermal properties

265

Both PILs exhibit sub-zero glass transition temperatures (Tg): –39 °C for [DPH][IBU]

266

and –17 °C for [DPH][NAP] (Figure 2a). The lower Tg of [DPH][IBU] suggests weaker cohesive

267

energy between the constituent species, which is consistent with its lower viscosity, higher

268

diffusion coefficient and ionic conductivity.21 No melting point was observed for either PILs.

269

This indicates that the PILs do not crystallize and consequently will not exhibit polymorphism,

270

which is a significant advantage for pharmaceutical manufacturing and stability.31 TGA results

271

suggested one-step decomposition with thermal stability up to 160 °C for both PILs (Figure 2b). 13 ACS Paragon Plus Environment

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272

For comparison, DPH is a liquid at room temperature, while its commercial form hydrochloride

273

salt, [DPH][HCl], is a crystalline solid with a melting point of 170 °C.8 Additionally, both NAP

274

and IBU are known to exhibit polymorphism.48, 49

Figure 2. (a) DSC thermograms of the PILs. The traces represent the second heating cycle (exothermic flow down). (b) Thermogravimetric curves of the IL samples, Tonset 5% is the temperature corresponding to 5% mass loss.

275

Ionicity of PILs

276

The ionicity of the PILs, i.e., the percentage of dissociated ions present in the system,

277

dictates both the physicochemical properties, such as density and viscosity, and the

278

pharmaceutical performance, such as membrane permeability.50 Low ionicity in PILs results in

279

low self-diffusion coefficients and high viscosities, as well as poor ionic conductivities.

280

However, for pharmaceutical PILs, lower ionicity is desirable because it favors higher

281

permeability through biological membranes compared to drugs in their ionic form.30

282

In the case of acid/base crystalline complexes, the proton transfer occurs more than 80%

283

of the cases for ∆pKa ≥ 3.51 The ∆pKa in the two PILs was ~3.9 or ~4.4 since the pKa’s of

284

protonated DPH, IBU, and NAP are 8.76±0.28, 4.84±0.30 and 4.41±0.10, respectively.

285

However, the FT-IR spectra indicated that the two PILs had relatively low ionicity (Figure 3).

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Molecular Pharmaceutics

286

The C=O stretch in the functional groups of COOH and COO- are clearly distinguished in the

287

range of 1500-1800 cm–1 for IBU/[Na][IBU] and NAP/[Na][NAP] (Figure 3a & 3b). The main

288

corresponding IR peak of PILs match well with the non-ionic forms of IBU or NAP, and only a

289

small absorbance shoulder corresponds to their ionic forms ([Na][IBU] /[Na][NAP]).

290

Additionally, the NH+ function group stretch (2700 - 2400 cm-1) observed in [DPH][HCl] is

291

absent in both PILs, suggesting little ionization of DPH in [DPH][IBU] and [DPH][NAP] as well

292

(Figure 3c). Collectively, the FTIR data show that both PILs are largely un-ionized. In DPH-

293

containing crystal structures, strong charge assisted N+–H···O or N+–H···Cl- hydrogen bonds are

294

usually observed.8 In contrast, the poor ionicity of the [DPH][IBU] and [DPH][NAP] PILs

295

suggested the major intermolecular interactions are O–H···N hydrogen bonding. Therefore, the

296

∆pKa rule for proton transfer in crystalline phases is not applicable to PILs.51

297

observation was made in the liquid lidocaine-fatty acid complexes, where the un-ionized

298

molecular form was observed when ∆pKa ≈ 3.36, 52

A similar

299

The ionicity of [DPH][IBU] and [DPH][NAP] PILs was quantified using an 1H NMR

300

method (see Supporting Information for the analysis).35 Chemical shifts of the conjugate acid

301

(δBH+) and base in the ionic liquid complex (δBPIL) were well-resolved, as shown in Table 1.

302

The two proton signals from the [DPH]+ cation spectrum used in the analysis were the methyl

303

and methine protons adjacent to the amine. The chemical shifts for the free base (δB) were

304

obtained from previous reports.20 The NMR analysis results (Table 1) show that both PILs

305

exhibit incomplete proton transfer from the two acids to the base, 8-10% in [DPH][IBU] and 6-

306

7% in [DPH][NAP].

307

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Page 16 of 32

(b)

(a)

(c)

308 309 310 311 312 313

Figure 3. FT-IR spectra in the 1800 – 1000 cm-1 range for a) [DPH][IBU], b) [DPH][NAP], and c) 2700 – 2400 cm-1 for both [DPH][IBU] and [DPH][NAP]. The dotted line represents the stretch of -COOH (red), -COO- (blue) functional groups.

Table 1. 1H NMR data and the percentage of ionized complex (% salt)

314 PIL

Proton NMR

δB (ppm)

δBPIL (ppm)

δBH+ (ppm)

%B

% salt

[DPH][IBU]

-CH2N(CH3)2

2.49

2.59

3.47

90

10

-CH2N(CH3)2

2.16

2.22

2.90

92

8

-CH2N(CH3)2

2.49

2.56

3.47

93

7

-CH2N(CH3)2

2.16

2.20

2.90

94

6

[DPH][NAP]

315

To further confirm the low ionicity of these PILs, self-diffusion coefficients, viscosities

316

and ionic conductivities were measured. The species in [DPH][IBU] (free ions, ion pairs, and 16 ACS Paragon Plus Environment

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Molecular Pharmaceutics

317

higher aggregates) diffuse much faster than those in [DPH][NAP], about an order of magnitude

318

faster at 50 oC (Figure 4a). Notably, these diffusion coefficients are significantly lower than the

319

ionic species (≈10–10 m2/s at room temperature) in alkylimidazolium bis(trifluoromethane

320

sulfonyl)imide PILs that exhibit high ionicity (> 60%).53 The DPH species in [DPH][NAP]

321

diffuse about ten times slower than those in [DPH][IBU] (Tables S2 and S3), which reflects the

322

lower ionicity and stronger ion-association in [DPH][NAP] (Table 1). The significantly higher

323

viscosities of [DPH][NAP] than [DPH][IBU], e.g., two orders of magnitude difference at 25 °C,

324

(Figure 4b) also suggests stronger intermolecular interactions in [DPH][NAP].21

325 326 327 328

Figure 4. a) Temperature dependence of summation of cationic and anionic diffusion coefficients, b) shear viscosity of the PILs at a shear rate of 1 s–1.

329

Low ionicity of a PIL has its biggest impact on the ionic conductivity, since transport of

330

ion-pairs or other neutral ion-aggregates does not contribute to it. Figure 5 summarizes the ionic

331

conductivity as a function of temperature. The order of magnitude lower ionic conductivity for

332

[DPH][NAP] compared to [DPH][IBU] can be attributed to the combined effects of a) lower

333

diffusivities (Figure 4a) and higher viscosity (Figure 4b) of [DPH][NAP], b) higher glass

334

transition temperature (Figure 2a), and c) lower concentration of free ions (Tables S1-S2). Figure

335

5 also provides a comparison of the ionic conductivity measured by impedance spectroscopy

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Page 18 of 32

336

(open symbols) and the ionic conductivity, σ, calculated using diffusion coefficients (filled

337

symbols) from PFG-NMR experiments via the Nernst−Einstein equation: σ =

F2 + + c D + c−D− RT

(

)

(3)

338

where c+ and c– are the molar concentration of the ionic species, F is Faraday’s constant, R is the

339

gas constant and T is temperature. Ionic conductivity estimation using eq. 3 assumes that the

340

PILs are composed of fully dissociated free ions alone. Comparing the measured ionic

341

conductivity to the calculated value indicates that less than 10% of [DPH][IBU] and less than 5%

342

of [DPH][NAP] exists as free ions. This is consistent with the ionicity estimated using NMR

343

analysis (Table 1).

344 345 346 347 348

Figure 5. Temperature dependence of measured ionic conductivity (open symbols) and calculated ionic conductivity (filled symbols) using PFG-NMR diffusion coefficients via the Nernst−Einstein equation for (a) [DPH][IBU] and (b) [DPH][NAP] PILs.

349

The low ionicity firmly established by complementary techniques suggests that both

350

liquids are expected to contain predominantly H-bonded A − H ··· B complexes instead of ions

351

resulting from complete transfer of proton.

352

Hygroscopicity

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Molecular Pharmaceutics

353

Absorbed moisture affects the physical and chemical properties of PILs,54 which can

354

present a problem to pharmaceutical processing. The use of magnesium sulfate during PIL

355

preparation was effective in removing residual water since TGA data of these samples showed

356

no loss in weight up to 120 oC (Figure 2b). Figure 6a reveals that these PILs are moderately

357

hygroscopic based on the criteria from the European Pharmacopeia.55 The PILs gained weight

358

more than their surface absorption capacity with no hysteresis between sorption and desorption

359

curves, implying that water penetrated into the bulk of the PILs and that the curves correspond to

360

thermodynamic equilibrium between solution composition and water activity. The absorbed

361

water is less than 1% at RH below 20%. Thus, all the characterization experiments were

362

conducted in a low RH (5–15%) environment to minimize impact of water on analyses. As a

363

result, we did not encounter any processing problems associated with hygroscopicity.

364

Moisture sorption isotherms of both [Na][IBU] and [Na][NAP] suggested physical

365

stability problems (Figure S6), where anhydrous [Na][IBU] took up a significant amount of

366

water when the RH was raised above 25% during sorption. The weight increase matched well

367

with the theoretical water content of a dihydrate form (15.7%). On desorption, the [Na][IBU]

368

dihydrate maintained stability over the 10 – 95% RH range but lost water below 10% to form the

369

anhydrate. [Na][NAP] undergoes a more complicated solid-state transformation during the

370

moisture sorption and desorption cycle. The anhydrous [Na][NAP] transformed to dihydrate

371

(theoretical water content 15.6 %) in the RH range of 60% – 70% and then a tetrahydrate

372

(theoretical water content 31.2 %) in the RH range of 75% – 95% (Figure S6). On desorption, the

373

[Na][NAP] tetrahydrate started to lose water when the RH was below 55% and maintained water

374

close to the dihydrate between 30% and 45% RH. Further decrease in RH led to gradual loss of

375

water with no distinct plateau region until 5%, at which all water was lost to form the anhydrate.

376

This is in excellent agreement with that reported in the literature.56 The [DPH][HCl] deliquesced

377

when the RH was higher than 85% (Figure S6), which is consistent with its high aqueous

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Page 20 of 32

378

solubility.8 The lack of such physical form changes is an advantage of the two PILs over their

379

parent salts.

380 (a)

(b)

381 382 383

Figure 6. (a) Moisture sorption and desorption of PILs, (b) dependence of IL-water contact angle on time.

384 385

Wettability and solubility

386

The relatively low water contact angles (CA) of the PILs suggest good wettability (Figure

387

6b). The CAs of both PILs decreased with time, but the CA of [DPH][IBU] was always much

388

lower than that of [DPH][NAP] (Figure 6b), suggesting better wettability for [DPH][IBU]. The

389

CA of [DPH][IBU] is also significantly lower than that of IBU (88°),57 suggesting improved

390

wettability upon PIL formation.

391

Both IBU and NAP free acids are poorly soluble drugs with pH-dependent solubility

392

profiles, and several approaches have been attempted to address the solubility issues.58-60 In a

393

simplified thermodynamic solubility model, both the solvation and crystal lattice energy are key

394

factors determining the crystal solubility.61 Because the formation of PILs eliminates the lattice

395

energies of IBU and NAP crystals, a higher solubility is expected for the PILs. In fact, the

396

thermodynamic solubility of [DPH][IBU] (8.3 ± 0.5 mM) and [DPH][NAP] (4.1 ± 0.8 mM) in 20 ACS Paragon Plus Environment

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Molecular Pharmaceutics

397

water is about eight to ten times greater than IBU (1.03 ± 0.05 mM) and NAP (0.46 ± 0.10 mM),

398

respectively. However, the pH was shifted after the solubility measurements, IBU (pH = 5.0),

399

NAP (pH = 5.2), [DPH][NAP] (pH = 6.4), and [DPH][IBU] (pH = 6.1). At the same equilibrium

400

solution pH of ~6.8, using a phosphate buffer as a medium, the solubility followed the order:

401

IBU (35.8 ± 7.9 mM) >NAP (11.6 ± 1.0 mM) > [DPH][IBU] (9.2 ± 0.1 mM) > [DPH][NAP]

402

(7.6 ± 1.1 mM). At pH 2, solubility of PILs could not be determined because of spontaneous

403

conversion to corresponding free acid, which means that solubility of PILs is greater than that of

404

free acids. The bioavailability of DPH is not affected by the choice of forms because its

405

therapeutic dose is fully dissolved regardless of the forms studied here.

406

Dissolution

407

With high water solubility and good wettability, the PILs were expected to exhibit a

408

favorable dissolution rate in water or low pH media. However, [DPH][IBU] and [DPH][NAP]

409

PILs in pH 6.8 medium displayed slow dissolution under the sink condition (Figure 7). This is

410

attributed to the lower solubility at 6.8 pH and small surface area of the PIL droplets. Both PILs

411

formed large liquid drops in the dissolution media upon disintegration of the capsule shell. The

412

drug concentration gradually increased, but only about 50% of the drug was released over 35

413

min.

414

Formulation development

415

As discussed above, the common solid forms of the three drugs, IBU, NAP, DPH,

416

[Na][IBU], [Na][NAP], and [DPH][HCl] all exhibit major deficiencies in pharmaceutical

417

properties. Formation of an PIL provides an alternative approach for modifying the state of

418

drugs, and therefore pharmaceutically important properties. However, compared to solids, one

419

disadvantage of a PIL is the handling difficulty during pharmaceutical manufacturing.28, 29 To

420

address this limitation and to harness the potential of these two PILs to improve drug delivery, a

421

particle engineering strategy was applied to both improve the processability, and to enhance the

422

dissolution by increasing surface area. 21 ACS Paragon Plus Environment

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423

Page 22 of 32

Mesoporous carrier-based formulation strategies have been used to deliver low-dose

424

drugs, taking advantages of their high specific surface area and excellent flowability.62,

425

Dispersing these PILs into the porous silica carrier is expected to be effective in improving

426

manufacturability, dissolution rates, and bioavailability. In fact, the PIL-carrier composites

427

displayed much better flowability than Avicel PH102, a commonly used reference powder that

428

marks acceptable flowability for high speed tableting (Table 2).64 Therefore, this particle

429

engineering strategy led to excellent flowability, which is expected to yield reproducible die

430

filling performance.65 In addition to ffc, other flow parameters, such as the effective angle of

431

internal friction, the angle of linearized yield locus, and angle of internal friction at steady state

432

flow, are also lower than those of Avicel PH102.

433

behavior of the composite powders suitable for high speed tablet manufacturing and capsule

434

filling.

65

63

Thus, they also suggest free-flowing

435

The absence of any crystalline characteristic peak in the PXRD patterns of PIL in carrier

436

indicates the drugs were in an amorphous state (Figure S7). Therefore, loading PILs into porous

437

carrier did not induce crystallization. In contrast to pure [DPH][NAP] PIL, the composite

438

formulation showed significantly improved dissolution rate in the single chamber dissolution

439

test, where the two drugs are released close to a 1:1 ratio (Figure 7a and 7b). This is reasonable

440

since no precipitation occurred during the entire course of dissolution. In all cases, nearly 90% of

441

the drug was released for [DPH][IBU] and [DPH][NAP] PIL capsules in 15 min.

442

dissolution profiles of [DPH][IBU] and [DPH][NAP] PILs composites with the carrier did not

443

significantly differ (Figure 7), despite the very different viscosity, diffusion coefficient, and

444

wettability.

The

445 446 447 448 449 22 ACS Paragon Plus Environment

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450

Molecular Pharmaceutics

Table 2. Flowability of IL formulations tested at 1kPa preshear normal stress.

Angle of linearized yield locus (o)

Angle of internal friction at steady state flow (o)

Sample name

ffc

Bulk density (mg/mL)

Effective angle of internal friction (o)

[DPH][IBU] IL formulation

20.00±1.73

307 ± 13

27.7±0.68

26.7±0.7

26.1±0.8

[DPH][NAP] IL formulation

19.3±0.6

296 ± 2

27.8±0.1

26.3±0.1

26.0±0.1

5.5 ± 0.42

373 ± 6

42.5 ± 0.5

38.0 ± 0.4

39.0 ± 0.4

Avicel PH102

65

451 (a)

(b)

(c)

452 453 454 455

Figure 7. Drug release profiles of a) [DPH] and b) [NAP] from [DPH][NAP] PIL and c) [DPH][IBU] PIL and PIL-carrier composite in pH 6.8 buffer solution. The dashed lines indicate the expected drug concentration upon full release. 23 ACS Paragon Plus Environment

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Page 24 of 32

456

When [DPH][NAP] PIL was assessed using the ASD apparatus, both DPH and NAP were

457

released more rapidly from the composite in the stomach chamber than the pure PIL (Figures 8a

458

and 8b). Also, increased AUC and Cmax as well as decreased Tmax were observed in the drug

459

release profiles obtained in the duodenum chamber for both NAP and DPH (Figure 8c and 8d,

460

Table 3). Since both DPH and NAP have good permeability and their absorption is limited by

461

dissolution, the better drug release profiles in the duodenum chamber indicate improved

462

bioavailability of the composite. (a)

Stomach

(b)

(c)

Duodenum

(d)

463 464 465 466

Figure 8. ASD profile of a) [NAP] and b) [DPH] from [DPH][NAP] PIL and PIL-carrier composite in the stomach and c) [NAP] and d) [DPH] from [DPH][NAP] PIL and PIL-carrier composite in the duodenum (n = 3).

467 24 ACS Paragon Plus Environment

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468

Molecular Pharmaceutics

Table 3. Simulated pharmacokinetic parameters of [DPH][NAP] PIL and PIL formulation (n=3) NAP

DPH

PIL

PIL-carrier

PIL

PIL-carrier

Tmax (min)

43±10

13.0±3

36±5

16±4

Cmax (mM)

0.03±0.01

0.13±0.03

0.11±0.01

0.20±0.03

AUC0-t (mM *min)

2.9±0.4

9± 1

5± 2

6 ±2

AUC0-inf (mM *min)

4.1±0.2

9± 1

6± 2

6 ±2

469 470

A rapid decrease in NAP concentration in the stomach occurred after 2 min, which may

471

indicate precipitation of the poorly soluble NAP. As discussed before, NAP and IBU exhibited

472

pH-dependent solubility profiles, whereas DPH is highly soluble over the whole pH range. We

473

hypothesized that the fast release of NAP from PIL led to a solution concentration much higher

474

than the saturation solubility of NAP at pH 2. The high degree of supersaturation led to

475

precipitation of NAP, which may cover the PIL surface to further retard NAP release. To test this

476

hypothesis, a few drops of dissolution media (pH = 2.0) were added to the PILs on a glass slide,

477

which was observed under a polarized light microscope. Precipitation of crystalline solids

478

happened within 2 mins. The precipitate was confirmed to be NAP free acid by PXRD (Figure

479

S8).

480

observation supports the hypothesis that precipitation of NAP was responsible for the observed

481

sharp decrease in the NAP concentration in the stomach chamber. Similar observations were

482

also made for [DPH][IBU] PIL (Figure S9). Such crystallization during dissolution can be

483

prevented by using appropriate polymers or other crystallization inhibitors.66-68

The amount of crystalline precipitate continued to grow with time (Figure 9). This

484 485

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Page 26 of 32

486 487 488

Figure 9. Polarized light microscope images showing the crystallization during dissolution of [DPH][NAP] PIL in pH 2.0 solution. The scale bar represents 500 µm.

489 490

CONCLUSIONS

491

Structural information, extracted from NMR spectroscopy, mass spectrometry, elemental

492

analysis, and infrared and Raman spectroscopy, confirmed that PILs of DPH with IBU and NAP

493

were successfully prepared. These two PILs exhibited unexpectedly low ionicity, which was

494

confirmed by a suite of complementary techniques. Excellent thermal stability, high viscosity,

495

improved water solubility, better water wettability, and absence of crystallization at room

496

temperature and high RHs, make these PILs an attractive approaches to alter the

497

physicochemical and biopharmaceutical properties of drugs. A mesoporous silica carrier was

498

used to overcome the challenges associated with handling and small droplet surface areas of the

499

PILs. The resulting free-flowing PIL-carrier composite powders were successfully used to

500

prepare capsules that exhibited rapid dissolution and improved bioavailability over pure PIL.

501 502

ASSOCIATED CONTENT

503

Supporting Information

504

NMR spectra, UV spectra, powder X-ray diffraction of PIL formulations and precipitate,

505

elemental analyses, diffusion coefficients, moisture sorption and desorption, polarized light

506

microscope image, and ionicity estimated using NMR analysis. This information is available free

507

of charge via the Internet at http://pubs.acs.org 26 ACS Paragon Plus Environment

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Molecular Pharmaceutics

508 509

ACKNOWLEDGEMENTS

510

Part of this work was carried out in the College of Science and Engineering Characterization

511

Facility, University of Minnesota, which has received capital equipment funding from the NSF

512

through the UMN MRSEC program under Award Number DMR-1420013. Partial funding for

513

this work was provided by the National Science Foundation (DMR-1609459 and DMR-

514

1707578). The authors thank Prof. Philippe Bühlmann for access to impedance spectroscopy

515

equipment.

516 517

REFERENCES

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1. Lehár, J.; Krueger, A. S.; Avery, W.; Heilbut, A. M.; Johansen, L. M.; Price, E. R.; Rickles, R. J.; Short Iii, G. F.; Staunton, J. E.; Jin, X. Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat. Biotechnol. 2009, 27, 659-666. 2. Jia, J.; Zhu, F.; Ma, X.; Cao, Z. W.; Li, Y. X.; Chen, Y. Z. Mechanisms of drug combinations: Interaction and network perspectives. Nat. Rev. Drug Discov. 2009, 8, 111-128. 3. Bangalore, S.; Kamalakkannan, G.; Parkar, S.; Messerli, F. H. Fixed-dose combinations improve medication compliance: A meta-analysis. Am. J. Med. 2007, 120, 713-719. 4. Gautam, C. S.; Saha, L. Fixed dose drug combinations (fdcs): Rational or irrational: A view point. Br. J. Clin. Pharmacol. 2008, 65, 795-796. 5. Ollendorf, D. A.; Sandhu, A. T.; Pearson, S. D. Sacubitril-valsartan for the treatment of heart failure: Effectiveness and value. JAMA Intern. Med. 2016, 176, 249-250. 6. McMurray, J. J.; Packer, M.; Desai, A. S.; Gong, J.; Lefkowitz, M. P.; Rizkala, A. R.; Rouleau, J. L.; Shi, V. C.; Solomon, S. D.; Swedberg, K. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med. 2014, 371, 993-1004. 7. Kong, D.-X.; Li, X.-J.; Zhang, H.-Y. Where is the hope for drug discovery? Let history tell the future. Drug Discov. Today 2009, 14, 115-119. 8. Wang, C.; Paul, S.; Wang, K.; Hu, S.; Sun, C. C. Relationships among crystal structures, mechanical properties, and tableting performance probed using four salts of diphenhydramine. Cryst. Growth Des. 2017, 17, 6030-6040. 9. Simon, F., The trouble with making combination drugs. Nature Publishing Group: 2006. 10. Chang, S.-Y.; Li, J.-x.; Sun, C. C. Tensile and shear methods for measuring strength of bilayer tablets. Int. J. Pharm. 2017, 523, 121-126. 11. Desiraju, G. R. Crystal engineering: From molecule to crystal. J. Am. Chem. Soc. 2013, 135, 9952-9967. 12. Duggirala, N. K.; Perry, M. L.; Almarsson, O.; Zaworotko, M. J. Pharmaceutical cocrystals: Along the path to improved medicines. Chem. Comm. 2016, 52, 640-655. 27 ACS Paragon Plus Environment

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13. Almansa, C.; Mercè, R.; Tesson, N.; Farran, J.; Tomàs, J.; Plata-Salamán, C. R. Cocrystal of tramadol hydrochloride–celecoxib (ctc): A novel api–api co-crystal for the treatment of pain. Cryst. Growth Des. 2017, 17, 1884-1892. 14. Aitipamula, S.; Banerjee, R.; Bansal, A. K.; Biradha, K.; Cheney, M. L.; Choudhury, A. R.; Desiraju, G. R.; Dikundwar, A. G.; Dubey, R.; Duggirala, N.; Ghogale, P. P.; Ghosh, S.; Goswami, P. K.; Goud, N. R.; Jetti, R. R. K. R.; Karpinski, P.; Kaushik, P.; Kumar, D.; Kumar, V.; Moulton, B.; Mukherjee, A.; Mukherjee, G.; Myerson, A. S.; Puri, V.; Ramanan, A.; Rajamannar, T.; Reddy, C. M.; Rodriguez-Hornedo, N.; Rogers, R. D.; Row, T. N. G.; Sanphui, P.; Shan, N.; Shete, G.; Singh, A.; Sun, C. C.; Swift, J. A.; Thaimattam, R.; Thakur, T. S.; Kumar Thaper, R.; Thomas, S. P.; Tothadi, S.; Vangala, V. R.; Variankaval, N.; Vishweshwar, P.; Weyna, D. R.; Zaworotko, M. J. Polymorphs, salts, and cocrystals: What’s in a name? Cryst. Growth Des. 2012, 12, 2147-2152. 15. Wang, B.; Qin, L.; Mu, T.; Xue, Z.; Gao, G. Are ionic liquids chemically stable? Chem. Rev. 2017, 117, 7113-7131. 16. Park, M. J.; Choi, I.; Hong, J.; Kim, O. Polymer electrolytes integrated with ionic liquids for future electrochemical devices. J. Appl. Polym. Sci. 2013, 129, 2363-2376. 17. Armand, M.; Endres, F.; MacFarlane, D. R.; Ohno, H.; Scrosati, B. Ionic-liquid materials for the electrochemical challenges of the future. Nat. Mater. 2009, 8, 621. 18. Chopade, S. A.; Anderson, E. L.; Schmidt, P. W.; Lodge, T. P.; Hillmyer, M. A.; Bühlmann, P. Self-supporting, hydrophobic, ionic liquid-based reference electrodes prepared by polymerization-induced microphase separation. ACS Sens. 2017, 2, 1498-1504. 19. Lodge, T. P.; Ueki, T. Mechanically tunable, readily processable ion gels by selfassembly of block copolymers in ionic liquids. Acc. Chem. Res. 2016, 49, 2107-2114. 20. Frizzo, C. P.; Wust, K.; Tier, A. Z.; Beck, T. S.; Rodrigues, L. V.; Vaucher, R. A.; Bolzan, L. P.; Terra, S.; Soares, F.; Martins, M. A. Novel ibuprofenate-and docusate-based ionic liquids: Emergence of antimicrobial activity. RSC Adv. 2016, 6, 100476-100486. 21. Greaves, T. L.; Drummond, C. J. Protic ionic liquids:  Properties and applications. Chem. Rev. 2008, 108, 206-237. 22. Marrucho, I.; Branco, L.; Rebelo, L. Ionic liquids in pharmaceutical applications. Annu. Rev. Chem. Biomol. Eng. 2014, 5, 527-546. 23. Cho, J. H.; Lee, J.; Xia, Y.; Kim, B.; He, Y.; Renn, M. J.; Lodge, T. P.; Frisbie, C. D. Printable ion-gel gate dielectrics for low-voltage polymer thin-film transistors on plastic. Nat. Mater. 2008, 7, 900-906. 24. Tang, B.; Schneiderman, D. K.; Zare Bidoky, F.; Frisbie, C. D.; Lodge, T. P. Printable, degradable, and biocompatible ion gels from a renewable aba triblock polyester and a low toxicity ionic liquid. ACS Macro Letters 2017, 6, 1083-1088. 25. Patel, A. A.; Dave, R. H. Development and characterization of innovative liquid salt based formulations of sparingly soluble drugs. Int. J. Pharm. Sci. Res 2015, 6, 2316-2327. 26. Chowdhury, M. R.; Moshikur, R. M.; Wakabayashi, R.; Tahara, Y.; Kamiya, N.; Moniruzzaman, M.; Goto, M. Ionic-liquid-based paclitaxel preparation: A new potential formulation for cancer treatment. Mol. Pharmaceutics 2018, 15, 2484-2488. 27. Sahbaz, Y.; Nguyen, T.-H.; Ford, L.; McEvoy, C. L.; Williams, H. D.; Scammells, P. J.; Porter, C. J. H. Ionic liquid forms of weakly acidic drugs in oral lipid formulations: Preparation, characterization, in vitro digestion, and in vivo absorption studies. Mol. Pharmaceutics 2017, 14, 3669-3683.

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28. Shamshina, J. L.; Kelley, S. P.; Gurau, G.; Rogers, R. D. Chemistry: Develop ionic liquid drugs. Nature News 2015, 528, 188. 29. Shamshina, J. L.; Barber, P. S.; Rogers, R. D. Ionic liquids in drug delivery. Expert Opin. Drug Deliv. 2013, 10, 1367-1381. 30. Stoimenovski, J.; MacFarlane, D. R. Enhanced membrane transport of pharmaceutically active protic ionic liquids. Chem. Comm. 2011, 47, 11429-11431. 31. Stoimenovski, J.; MacFarlane, D. R.; Bica, K.; Rogers, R. D. Crystalline vs. Ionic liquid salt forms of active pharmaceutical ingredients: A position paper. Pharm. Res. 2010, 27, 521526. 32. Yoshizawa, M.; Xu, W.; Angell, C. A. Ionic liquids by proton transfer:  Vapor pressure, conductivity, and the relevance of δpka from aqueous solutions. J. Am. Chem. Soc. 2003, 125, 15411-15419. 33. Shen, M.; Zhang, Y.; Chen, K.; Che, S.; Yao, J.; Li, H. Ionicity of protic ionic liquid: Quantitative measurement by spectroscopic methods. J. Phys. Chem. B 2017, 121, 1372-1376. 34. Stoimenovski, J.; Dean, P. M.; Izgorodina, E. I.; MacFarlane, D. R. Protic pharmaceutical ionic liquids and solids: Aspects of protonics. Faraday Discuss. 2012, 154, 335352. 35. Moreira, D. N.; Fresno, N.; Pérez-Fernández, R.; Frizzo, C. P.; Goya, P.; Marco, C.; Martins, M. A.; Elguero, J. Brønsted acid–base pairs of drugs as dual ionic liquids: Nmr ionicity studies. Tetrahedron 2015, 71, 676-685. 36. Bica, K.; Shamshina, J.; Hough, W. L.; MacFarlane, D. R.; Rogers, R. D. Liquid forms of pharmaceutical co-crystals: Exploring the boundaries of salt formation. Chem. Comm. 2011, 47, 2267-2269. 37. Wang, H.; Gurau, G.; Shamshina, J.; Cojocaru, O. A.; Janikowski, J.; MacFarlane, D. R.; Davis, J. H.; Rogers, R. D. Simultaneous membrane transport of two active pharmaceutical ingredients by charge assisted hydrogen bond complex formation. Chem. Sci. 2014, 5, 34493456. 38. Smith, E. L.; Abbott, A. P.; Ryder, K. S. Deep eutectic solvents (dess) and their applications. Chem. Rev. 2014, 114, 11060-11082. 39. Wang, C.; Perumalla, S. R.; Lu, R.; Fang, J.; Sun, C. C. Sweet berberine. Cryst. Growth Des. 2016, 16, 933-939. 40. Wang, C.; Perumalla, S. R.; Sun, C. C. Anion exchange reaction for preparing acesulfame solid forms. Cryst. Growth Des. 2018. DOI: 10.1021/acs.cgd.8b00106. 41. Chopade, S. A.; So, S.; Hillmyer, M. A.; Lodge, T. P. Anhydrous proton conducting polymer electrolyte membranes via polymerization-induced microphase separation. ACS Appl. Mater. Interfaces 2016, 8, 6200-6210. 42. Wu, D.; Chen, A.; Johnson, C. S. An improved diffusion-ordered spectroscopy experiment incorporating bipolar-gradient pulses. J. Magn. Reson., Ser A 1995, 115, 260-264. 43. Chopade, S. A.; Au, J. G.; Li, Z.; Schmidt, P. W.; Hillmyer, M. A.; Lodge, T. P. Robust polymer electrolyte membranes with high ambient-temperature lithium-ion conductivity via polymerization-induced microphase separation. ACS Appl. Mater. Interfaces 2017, 9, 1456114565. 44. Carino, S. R.; Sperry, D. C.; Hawley, M. Relative bioavailability of three different solid forms of pnu‐141659 as determined with the artificial stomach‐duodenum model. J. Pharm. Sci. 2010, 99, 3923-3930.

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45. Hawley, M.; Morozowich, W. Modifying the diffusion layer of soluble salts of poorly soluble basic drugs to improve dissolution performance. Mol. Pharmaceutics 2010, 7, 14411449. 46. Polster, C. S.; Atassi, F.; Wu, S.-J.; Sperry, D. C. Use of artificial stomach− duodenum model for investigation of dosing fluid effect on clinical trial variability. Mol. Pharmaceutics 2010, 7, 1533-1538. 47. Zhang, Y.; Huo, M.; Zhou, J.; Xie, S. Pksolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in microsoft excel. Comput. Methods Programs Biomed. 2010, 99, 306-314. 48. Song, J.-S.; Sohn, Y.-T. Crystal forms of naproxen. Arch. Pharm. Res. 2011, 34, 87. 49. Dudognon, E.; Danède, F.; Descamps, M.; Correia, N. T. Evidence for a new crystalline phase of racemic ibuprofen. Pharm. Res. 2008, 25, 2853-2858. 50. Swarbrick, J.; Lee, G.; Brom, J.; Gensmantel, N. P. Drug permeation through human skin ii: Permeability of ionizable compounds. J. Pharm. Sci. 1984, 73, 1352-1355. 51. Cruz-Cabeza, A. J. Acid-base crystalline complexes and the pka rule. CrystEngComm 2012, 14, 6362-6365. 52. Kelley, S. P.; Narita, A.; Holbrey, J. D.; Green, K. D.; Reichert, W. M.; Rogers, R. D. Understanding the effects of ionicity in salts, solvates, co-crystals, ionic co-crystals, and ionic liquids, rather than nomenclature, is critical to understanding their behavior. Cryst. Growth Des. 2013, 13, 965-975. 53. Tokuda, H.; Hayamizu, K.; Ishii, K.; Susan, M. A. B. H.; Watanabe, M. Physicochemical properties and structures of room temperature ionic liquids. 2. Variation of alkyl chain length in imidazolium cation. J. Phys. Chem. B 2005, 109, 6103-6110. 54. Widegren, J. A.; Laesecke, A.; Magee, J. W. The effect of dissolved water on the viscosities of hydrophobic room-temperature ionic liquids. Chem. Comm. 2005, 12, 1610-1612. 55. Newman, A. W.; Reutzel‐Edens, S. M.; Zografi, G. Characterization of the “hygroscopic” properties of active pharmaceutical ingredients. J. Pharm. Sci. 2008, 97, 10471059. 56. Raijada, D.; Bond, A. D.; Larsen, F. H.; Cornett, C.; Qu, H.; Rantanen, J. Exploring the solid-form landscape of pharmaceutical hydrates: Transformation pathways of the sodium naproxen anhydrate-hydrate system. Pharm. Res. 2013, 30, 280-289. 57. Talukder, R.; Reed, C.; Dürig, T.; Hussain, M. Dissolution and solid-state characterization of poorly water-soluble drugs in the presence of a hydrophilic carrier. AAPS PharmSciTech 2011, 12, 1227-1233. 58. Rasenack, N.; Müller, B. W. Dissolution rate enhancement by in situ micronization of poorly water-soluble drugs. Pharm. Res. 2002, 19, 1894-1900. 59. Gupta, U.; Agashe, H. B.; Asthana, A.; Jain, N. Dendrimers: Novel polymeric nanoarchitectures for solubility enhancement. Biomacromolecules 2006, 7, 649-658. 60. Merisko-Liversidge, E.; Liversidge, G. G.; Cooper, E. R. Nanosizing: A formulation approach for poorly-water-soluble compounds. Eur. J. Pharm. Sci. 2003, 18, 113-120. 61. Docherty, R.; Pencheva, K.; Abramov, Y. A. Low solubility in drug development: De‐ convoluting the relative importance of solvation and crystal packing. J. Pharm. Pharmacol. 2015, 67, 847-856. 62. Sun, W.-J.; Aburub, A.; Sun, C. C. Particle engineering for enabling a formulation platform suitable for manufacturing low-dose tablets by direct compression. J. Pharm. Sci. 2017, 106, 1772-1777. 30 ACS Paragon Plus Environment

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63. Sun, W.-J.; Aburub, A.; Sun, C. C. A mesoporous silica based platform to enable tablet formulations of low dose drugs by direct compression. Int. J. Pharm. 2018, 539, 184-189. 64. Sun, C. C. Setting the bar for powder flow properties in successful high speed tableting. Powder Technol. 2010, 201, 106-108. 65. Shi, L.; Chattoraj, S.; Sun, C. C. Reproducibility of flow properties of microcrystalline cellulose — avicel ph102. Powder Technol. 2011, 212, 253-257. 66. Yamashita, H.; Sun, C. C. Harvesting potential dissolution advantages of soluble cocrystals by depressing precipitation using the common coformer effect. Cryst. Growth Des. 2016, 16, 6719-6721. 67. Ullah, M.; Hussain, I.; Sun, C. C. The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance. Drug Development and Industrial Pharmacy 2016, 42, 969-976. 68. Yamashita, H.; Sun, C. C. Self-templating accelerates precipitation of carbamazepine dihydrate during the dissolution of a soluble carbamazepine cocrystal. CrystEngComm 2017, 19, 1156-1159.

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Synopsis Synergistic drug combinations of diphenhydramine with ibuprofen or naproxen formed protic ionic liquids (PIL). Loading PIL into a mesoporous carrier achieved free-flowing powders with rapid drug dissolution than corresponding PIL.

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