Screening, Preparation, and Characterization of Aceclofenac Cocrystals Sushma Verma1,2*, Arun Nanda3, S.P

Research Article Screening, preparation, and characterization of aceclofenac cocrystals Sushma Verma1,2*, Arun Nanda3, S.P. Basu1 ABSTRACT Aim: The aim of the present investigation was to prepare cocrystals of a poorly soluble biopharmaceutical classification system Class - II drug, aceclofenac after screening to enhance its solubility and in turn the bioavailability. Materials and Methods: The screening of the cocrystal formers was done by calculating the solubility parameters using Hoftyzer and Van Krevelen solubility parameters and slurry crystallization technique using seven cocrystal formers. Cocrystals of the drug were prepared using solvent evaporation technique using the selected cocrystal formers, that is, Gallic acid and nicotinamide in the stoichiometric ratio of 1:1. Characterization of the prepared cocrystals was done using differential scanning calorimetry, Fourier-transform infrared studies, X-ray diffraction, and scanning electron microscopic techniques. Conclusion: All the four characterization techniques confirmed the formation of cocrystals of the drug thereby establishing cocrystallization as the method for improving the physiochemical properties of an active pharmaceutical ingredient. KEY WORDS: Aceclofenac, Cocrystals, Hoftyzer, Slurry crystallization technique, Van Krevelen solubility parameters INTRODUCTION nonsteroidal anti-inflammatory drug of the phenylacetic acid group, possessing remarkable anti-inflammatory, Cocrystallization has gained immense attention in the analgesic, and antipyretic properties. It is used to treat last decade as a means of tailoring the physicochemical pain, inflammation, rheumatoid arthritis, osteoarthritis, properties, such as solubility and dissolution of and inflammatory disease of the joints. Being a BCS biopharmaceutical classification system (BCS) Class Class - II drug, it exhibits very slight solubility in water, - II drugs. It is the method of producing multicomponent poor flow properties and compression characteristics. crystals in which the individual neutral molecules, It shows an elimination half-life of 4 h, volume of that is, the active pharmaceutical ingredient and the distribution 25 L and 50% oral bioavailability.[3] pharmaceutically acceptable molecules, known as the Cocrystal formers are pharmacologically inactive pharmaceutical cocrystal former are held together in material, safe and generally with improved stoichiometric ratios by freely reversible, non-covalent physicochemical properties.[4] They can be screened using interactions hydrogen bonds.[1] Cocrystals which a number of approaches such as supramolecular synthon are generally solid at ambient temperature have the approach using Cambridge database structure, hydrogen ability to partially design the crystal architecture using bonding between the drug and the coformer, Hansen established crystal engineering principles including the solubility parameters, and virtual cocrystal screening design of supramolecular synthons, and conduction of methods. Here, we have used solubility parameters using screening studies to evaluate stoichiometric variations Hoftyzer and Van Krevelen solubility parameters and in cocrystal composition.[2] slurry crystallization technique as the screening methods for the screening of cocrystal conformers.[5] Aceclofenac (2-[(2, 6-dichlorophenyl) amine] phenylacetoxyacetic acid) is an orally effective MATERIALS AND METHODS Access this article online Materials Aceclofenac was generously gifted from Suraksha Website: jprsolutions.info ISSN: 0975-7619 Pharma, Hyderabad, India. Nicotinamide was 1Pharmacy Institute, NIET, Plot 19, KP-II Greater Noida, Uttar Pradesh, India, 2Faculty of Pharmacy, Dr. A.P.J. Abdul Kalam Technical University, Lucknow, Uttar Pradesh, India, 3Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, India *Corresponding author: Sushma Verma, Pharmacy Institute, NIET, Greater Noida, Uttar Pradesh – 201306, India. Phone: +91-9350953160. E-mail: [email protected] Received on: 17-08-2018; Revised on: 24-09-2018; Accepted on: 11-10-2018 Drug Invention Today | Vol 11 • Issue 1 • 2019 81 Sushma Verma et al. procured from Sigma Aldrich, India. Gallic acid, Where, t1 and t2 are carrier and drug, respectively. tartaric acid, and vanillic acid were supplied by CDH Materials with ∆δ ≤ 7MPa0.5 are miscible, while Chemicals, New Delhi. Urea, citric acid, and maleic systems with ∆δ ≥ 7MPa0.5 are immiscible. acid were purchased from Qualigens Fine Chemicals Pvt., Ltd., Mumbai, Maharashtra. Screening of Cocrystals Cocrystal screening of aceclofenac was conducted Selection of Suitable Drug Molecule and Cocrystal with seven cocrystal formers: Gallic acid, citric acid, Formers maleic acid, nicotinamide, D-tartaric acid, urea, and Suitable drug molecule and cocrystal formers were vanillic acid. A total of 14 combinations of host and selected on the basis of Hoftyzer and Van Krevelen a guest at a 1:1 and 1:2 molar ratios were dissolved solubility parameters. Hansen proposed that the in dimethyl sulfoxide (DMSO). Each DMSO solution total force of the various interactions can be divided containing a host and a guest mixture (4 mg) was into partial solubility parameters, that is, dispersion dispensed to 0.6-mL glass vials with screw caps [6] (δd), polar (δp), and hydrogen bonding (δh). The and then lyophilized at −20°C to get a dried mass. total solubility parameter (δt), also called the three- Cocrystallization was performed using different dimensional solubility parameter, can be defined as solvents covering a broad range of functional groups. follows: Each crystallization solvent was dispensed to the vials; the slurries were stored for 3 days at ambient 22205. δtd=+()δδδph+ temperature with slow shaking at 100 rpm. After observation under optical microscopy, the solids in These partial solubility parameters, that is, δ , δ , the vials were collected and subjected to subsequent d p analysis by powder X-ray diffraction (XRD).[10] and δh can be calculated using the combined group contribution methods of Van Krevelen–Hoftyzer and Preparation of Cocrystals Fedors,[7,8] as follows: Cocrystals of aceclofenac were prepared with nicotinamide [11] F and Gallic acid by a solvent evaporation technique. ∑i di δd = • Accurately weighed drug and coformer, 354 mg of V aceclofenac and 188 mg of Gallic acid (1:1 molar ∑i i ratio) were dissolved in ethanol and left for slow 05. evaporation. After 5 days the fine crystals were F 2 ()∑i pi obtained, which were collected into a tight container δ p = Vi and stored in desiccators. ∑i • Accurately weighed drug and coformers, 354 mg 05. of aceclofenac and 122 mg of nicotinamide (1:1 Eh molar ratio) were dissolved in ethanol. They were ∑i i δh = left for slow evaporation. The fine crystals were V ∑i i obtained after 5 days, which were collected into a tight container and stored in desiccators. Where i is the structural group within the molecule, Fourier-transform Infrared (FT-IR) Studies Fdi is the group contribution to the dispersion forces, Fpi is the group contribution to the polar forces, Fhi FT-IR spectra were obtained for the pure drug, is the group contribution to the hydrogen bonding coformer, and cocrystals. The spectra were recorded energy, and Vi is the group contribution to the molar in a PerkinElmer FT-IR spectrophotometer. Potassium volume. Van Krevelen and Hoftyzer have determined bromide pellet method was employed and background the miscibility of two compounds using the ∆δ ̅ factor, spectrum was collected under identical conditions. which can be calculated as follows: Each spectrum was derived from 16 single average scans collected in the range of 400–4000 cm−1 at the 2 2 20 ∆δ =[(-δδ)+(-δδ)+(-δδ)].5 −1 dd21 pp22hh1 spectral resolution of 2 cm . Differential Scanning Calorimetry Krevelen et al. then suggested that good miscibility will be achieved if ∆δ ≤ 5MPa0.5. Recently, Greenhalgh Differential scanning calorimeter (DSC) was et al.[9] used the difference in total solubility parameter performed using DSC-60 (Shimadzu, Tokyo, Japan) calorimeter to study the thermal behavior of drug between the drug and the carriers ∆δt as a tool to predict miscibility: alone, a mixture of drug and coformer and the prepared cocrystals. The instrument comprised of calorimeter ∆=δδ−δ (DSC 60), flow controller (60), thermal analyzer tt21t (TA 60), and operating software (TA 60). The samples 82 Drug Invention Today | Vol 11 • Issue 1 • 2019 Sushma Verma et al. were heated in hermetically sealed aluminum pans F ∑i di 0.5 under nitrogen flow (30 ml/min) at a scanning rate of δd ==21.754MPa V 5°C/min from 24 ± 1°C to 250°C. Empty aluminum ∑i i pan was used as a reference. 05. 2 Fp ()∑i i 0.5 XRD δ p = = 54. MPa V The XRD patterns of pure drug and the prepared ∑i i 05. cocrystals were recorded using Philips X-ray E ∑i diffractometer (Model: PW1710) with a copper target. hi 0.5 δh = = 9M.0 Pa The conditions were: Voltage −30 kV; current −30 mA; V ∑i i and scanning speed −1/min; temperature of acquisition: Room temperature; detector: Scintillation counter 2 2 2 0.5 0.5 detector; and sample holder: Non-rotating holder. δt= (δd +δp + δh ) = 24.153MPa Screening of Cocrystals Scanning Electron Microscopy The slurry crystallization technique was used for the The surface characteristics of the pure drug and cocrystal screening method. Cocrystal screening of a prepared crystals were studied by scanning electron poorly soluble BCS Class II drug was carried with seven microscope (SEM) (JEOL, JSM 50A, Tokyo, Japan)

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