Spherical Agglomeration of Platy Crystals: Curious Case of Etodolac

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Spherical Agglomeration of Platy Crystals: Curious Case of Etodolac Supriya Dattatray Jitkar, Rajesh Thipparaboina, Rahul B Chavan, and Nalini R. Shastri Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b00563 • Publication Date (Web): 24 May 2016 Downloaded from http://pubs.acs.org on May 28, 2016

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Crystal Growth & Design

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Spherical Agglomeration of Platy Crystals: Curious Case of Etodolac

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Supriya Jitkar$, Rajesh Thipparaboina$, Rahul B Chavan, Nalini R Shastri*

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Solid State Pharmaceutical Research Group (SSPRG), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India

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Graphical Abstract

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A curious observation showcasing agglomeration of platy crystals into spheroids is presented for

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the first time. This research presents a systematic flow of events in spherical crystallization

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deploying various polymers HPMC, HPC, PVP and copolymers PEG, PVA and Poloxamer. A

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unique combination of HPMC-HPC-PEG resulted in spheroids of thin plates with improved flow

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and dissolution, yielding blends suitable for direct compression with higher hardness at lower

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pressures.

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$

Both the authors contributed equally

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*Corresponding author. Dr. Nalini R Shastri

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Tel. +91-040-23423749 Fax. +91-040-23073751

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E-mail: [email protected], [email protected]

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Address: Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research (NIPER), Balanagar, Hyderabad, India, Pin Code – 500037.

ACS Paragon Plus Environment


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Supriya Jitkar$, Rajesh Thipparaboina$, Rahul B Chavan, Nalini R Shastri*

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$

Both the authors contributed equally

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*Corresponding author. Nalini R Shastri

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Tel. +91-040-23423749

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Fax. +91-040-23073751

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E-mail: [email protected], [email protected]

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Abstract

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The present study reports an intriguing case study of agglomeration of platy crystals

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into spheroids. Etodolac a non-steroidal anti-inflammatory drug is mainly used for rheumatoid

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arthritis, with emerging applications in management of prostate cancer and Alzheimer’s disease.

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It is a BCS class II drug with poor flow and compressibility issues. Recrystallization using

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various solvents resulted in platy crystals. Different polymers like hydroxypropyl cellulose

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(HPC), hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP), copolymers

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poly(ethylene glycol) (PEG 400), polyvinyl alcohol (PVA) and Poloxamer were explored at

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various concentrations and in different combinations to provide systematic inputs for the

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development of spherical agglomerates with improved optimal sphericity, dissolution, yield, and

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mechanical properties suitable for direct compression. Effects of different process parameters on

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agglomeration were studied. Agglomerates obtained were characterized using SEM, DSC, and P-

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XRD and were evaluated for enhancements in flow, compressibility and dissolution. All the

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agglomerates have shown improved flow properties and compressibility. Unlike plain drug, all

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spherical agglomerates have shown acceptable plastic behaviour during compression studies

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resulting in tablets at low pressures. Agglomerates developed using an unique combination of

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HPMC, HPC and PEG has shown 94 % drug release in 15 minutes. The recrystallized spherical

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agglomerates can be used as readily compressible material for continuous manufacturing.

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Keywords: Etodolac, spherical agglomeration, crystal engineering, dissolution, compressibility.


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1.0 Introduction

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Tablets are one of the most commonly used dosage forms due to low cost, ease of

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manufacturing and patient compliance. Direct compression is the simplest way to manufacture

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tablets with simple unit operations like sieving, blending and compression. Drugs with good

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compaction and flow properties are ideal for direct compression. Low dose drugs (segregation

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problems) and high dose drugs (with high bulk volume, poor compressibility and poor

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flowability) pose problems during direct compression. Various factors including crystal habit,

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amorphous nature, low density, surface free energy, surface polarity, preferred orientation of

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molecule and process parameters affect direct compression1. Development of readily

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compressible blends has been one of the core research areas in the pharmaceutical industry. It

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can be achieved by crystal habit modification,2 amorphization,1 particle engineering3 and use of

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co-processed excipients.4 Use of co-processed excipient increases the bulk of unit dosage form,

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whereas amorphous substances pose stability issues and display poor flow properties.

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Particle engineering using excipients has hence emerged as a prominent strategy to

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address flow and compressibility issues. It may also help in dissolution enhancement when

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hydrophilic excipients like hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP),

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hydroxypropyl cellulose (HPC), polyethylene glycol (PEG), polyvinyl alcohol (PVA) etc are

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incorporated during processing. Spherical crystallization is one such emerging particle

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engineering technique in which crystallization and agglomeration takes place simultaneously. It

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provides platform for the development of readily compressible materials with improved flow and

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dissolution aiding in development of blends for direct compression.5-7 It produces spherical

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particles with improved micromeritics which consequently influence physical and mechanical

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properties, rendering the drugs suitable for direct tabletting.8 It is a simple technique which

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involves dissolution of the drug in good solvent (solvent in which drug has good solubility)

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followed by addition of poor solvent (solvent in which drug has low solubility) along with

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bridging liquids like chloroform, dichloromethane (DCM), hexane, ethyl acetate, etc. under

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continuous stirring.9 Polymers are generally added to aqueous phase. Drugs like acebutalol,10

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bucillamine,11 celecoxib,12 aceclofenac,13 and albendazole14 have been engineered using similar

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strategy to overcome problems associated with solubility and compressibility.

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Etodolac was selected as model drug for this study. It is a non-steroidal anti-

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inflammatory drug, which acts through cyclooxygenase-II inhibition. It is primarily used in



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treatment of joint pain, arthritis and muscular disorders. Its activity is well documented in

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Alzheimer’s disease in combination with quercetin.15 Recent reports revealed its activity in

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melanoma and carcinoma in combination with propranolol.16 Patent has been filed for its activity

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against hyperplasia17 and multiple myeloma.18 It is chemically 2-(1,8-diethyl-4,9-dihydro-3H-

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pyrano[3,4-b]indol-1-yl)acetic acid having poor solubility and belongs to biopharmaceutical

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classification system (BCS) class II. Recommended dose for analgesic effect is 200 to 600 mg

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and for anticancer effect is 600 mg. It is a high dose drug used in chronic therapy, exhibiting

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poor compressibility and flow properties, thus posing problems during direct tabletting.

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Agglomeration of needles into spherical systems is well documented2, 9, 11, 12, 14, 19-21 but to

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date no existing literature has discussed agglomeration of plates into spheroids. A systematic

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study was designed to overcome the problem of poor compressibility and flow properties of

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etodolac through spherical crystallization. Current study explored the effect of different polymers

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(HPC, HPMC, and PVP), copolymers (PEG 400, PVA and Poloxamer) on agglomeration,

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sphericity, mechanical strength and dissolution of the drug. Various combinations of polymers

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were explored to develop spherical agglomerates with optimal sphericity, dissolution,

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mechanical properties and good yield.

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2.0 Materials and methods

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2.1 Materials

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Etodolac was purchased from Yarrow Chem Labs, Mumbai (India). HPMC (Methocel

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E3, E5 and E15) was obtained as gift samples from Colorcon Asia Private Limited (India). HPC

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(L, M and H grades) was kindly gifted by Nippon Soda Co., Ltd. (Japan). PVP (K17, K25 and

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K30 grades) was obtained as gift samples from BASF SE (Germany). Poloxamer (F127) was

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purchased from Sigma Aldrich (Germany). All the other chemicals and solvents used were of

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analytical grade.

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2.2 Methodology

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2.2.1 Solubility studies

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Preliminary solubility screening of etodolac was performed in different solvents to

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identify safer solvent as per ICH classification with optimal solubility. 500 mg of etodolac was

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taken in a screw capped glass vial and various solvents like methanol, ethanol, isopropyl alcohol

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(IPA), dichloromethane (DCM), chloroform, ethyl acetate, acetone, diethyl ether, acetonitrile,

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dimethyl sulphoxide, dimethyl formamide and dioxane were added in 50-100 µL increments.


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Visual analysis for undissolved drug was carried out post addition of each aliquot and vortexing

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for 5 min. Solubility point was identified as the volume required to obtain a visually clear

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solution.22

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2.2.2 Spherical crystallization

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2.2.2.1 Selection of solvent system

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Based on the observations from the solubility studies (table S1, Supplementary

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Information) and considering the safety as per ICH classification of residual solvents,

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preliminary agglomeration trials were conducted using different solvents like ethanol, IPA, and

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acetone (good solvents) with water (anti-solvent) to understand the crystal habit and

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agglomeration tendency of the drug.23

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2.2.2.2 Identification of agglomeration region

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Acetone, water and DCM were then selected as good solvent, bad solvent and bridging

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liquid respectively based on the results of preliminary studies. Ternary phase diagram was

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plotted by mixing water and acetone in different ratios 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2 and

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9:1. DCM was added drop wise with intermittent mixing. The volume of DCM required to obtain

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a clear solution for each ratio was noted. A ternary phase diagram of the solvents was plotted

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using PROSIM software to identify miscible and immiscible regions. Drug (200 mg) was

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dissolved in acetone, added to water under stirring, followed by dropwise addition of DCM for

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10 min. Based on the morphology of the product obtained; miscible region was further classified

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into agglomeration zone, pasty mass zone and non-crystallizing zone. Volume of DCM was

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further optimized to obtain spherical agglomeration region.

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2.2.2.3 Preparation of spherical agglomerates

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Etodolac (1 gm) was dissolved in 5 ml of acetone, and then added to 45 ml of aqueous

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solution of polymer under mechanical stirring at 700 rpm. DCM was added drop wise and

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continued stirring for 30 min using an overhead digital stirrer equipped with a propeller blade.

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Spherical agglomerates obtained were filtered, dried and stored in glass containers until further

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analysis.

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2.2.2.4 Screening of the different polymers

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Polymers play a crucial role in imparting mechanical strength and modifying dissolution

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properties. Hence, different polymers like HPC (L-low, M-medium and H-high viscosity grades),

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HPMC (E3, E5 and E15) and PVP (K17, K25 and K30) and co-polymers like PEG 400,



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Poloxamer (F127), and PVA were screened to get spherical agglomerates with acceptable size

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and improved pharmaceutical attributes. Polymers enlisted above were explored at different

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concentrations 0.1 %, 0.25 % and 0.5 % w/v. Co-polymers like PEG 400 (5 %, 10 % and 15 %),

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Poloxamer (0.1 %, 0.25 % and 0.5 %) and PVA (0.1 %, 0.25 % and 0.5 %) were also studied in

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various concentrations.

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3. Solid state characterization

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3.1 Microscopy

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Inverted microscope (Olympus) operating with Magnus Pro software was used to observe

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the crystals at different magnifications. Aspect ratio (defined as the ratio of length to width) and

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particle sizes were also determined (n = 50). Microscopic examination was carried out to

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evaluate the shape and size of the agglomerates obtained. Surface morphology of the optimized

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batches was observed by taking photographs of samples in Hitachi S-300 N SEM at a voltage of

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15 kV. Beforehand, the samples were mounted on alumina stubs using double adhesive tape.

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Photomicrographs were taken for each sample at different magnifications.

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3.2 Fourier transforms infrared spectroscopy (FTIR)

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Accurately weighed 2 mg of samples were mixed thoroughly with 100 mg of potassium

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bromide IR powder and compressed under vacuum at a pressure of 12 psi for 3 min. The

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resultant pellet was affixed in a suitable holder and the FTIR spectra were recorded in the range

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4000 to 400 cm–1.

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3.3 Differential Scanning calorimetry (DSC)

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Optimized formulations along with controls were analyzed using Mettler Toledo DSC

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system with Stare software to understand the thermal behaviour, polymorphic transformations

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and excipient incompatibility. Accurately weighed samples (5–10 mg) in 40 µL aluminium

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crimped pans with pinhole were scanned at a heating rate of 10 ºC/min over a temperature range

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of 35-200 ºC in nitrogen gas environment with a purging rate of 60 mL/min.

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3.3 Powder X-ray diffraction (P-XRD)

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P-XRD of samples was carried out using Ni filtered Cu-Kα radiation (wavelength =

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1.5406 Å). The data were recorded over an angular range of 10° to 40°, 2θ at a step time of 0.030

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steps/0.5 s. All P-XRD measurements were done at ambient temperature.

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4.0 Evaluation of pharmaceutical properties

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4.1 Micromeritics


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Angle of repose, Carr’s index and Hausner’s ratio were used to test flow of the

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agglomerates. Angle of repose was measured by fixed funnel method. Funnel (cone diameter 5

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cm and stem bore diameter 0.5 cm) was fixed at 2 cm height and the agglomerate sample was

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allowed to flow through funnel orifice to form a heap touching the tip of the funnel. Height of

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the pile (h) and radius of the circle (r) was measured to calculate angle of repose. An angle of

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repose up to 25 indicates good flow property whereas above 40 reflects poor flow.

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θ = tan-1 (h/r)

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Carr’s index or Hausner’s ratio were measured by calculating bulk density (BD) and tap density

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(TD). A Carr’s index below 15 is indicative of good flow while above 35 designates poor flow

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properties. Hausner’s ratio below 1.35 indicates good flow property of the material while that

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above 1.35 depicts poor flow. Weighed amount of the agglomerates was poured into a measuring

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cylinder and the BD was calculated from ratio of mass to volume. It was then tapped until no

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more reduction in the volume of the powder was observed; TD was calculated from ratio of mass

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and tapped volume. From BD and TD, Carr’s index and Hausner’s ratio were determined using

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following equations.4, 24

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Carr’s index = (BD - TD)/TD * 100

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Hausner’s ratio = TD/BD

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4.2 Compressibility Studies

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Compressibility of the drug and agglomerates was evaluated by Well’s method.4 This

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method contains three variables (A, B, C) depending on the dwell time and the blending time.

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500 mg of the sample was mixed with 5 mg of magnesium stearate and blended for 5 min (A);

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for 5 min (B) and 30 min (C). The blends were then compressed using a 13 mm die at 100

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kg/cm2 for a dwell time of 2s, 30s and 2s for A, B, C respectively. Compacts formed were

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equilibrated for 24 h and their diametrical crushing strength was determined using LABINDIA

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hardness tester. Elastic materials generally show capping tendency due to recoil, in such cases A

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and C compacts will cap or laminate and B will maintain the integrity but forms a weak compact.

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Whereas, for plastic and fragmenting materials, the compact strength is B > A > C and A = B =

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C respectively. Well’s protocol used for the study is provided in table S2 (Supplementary

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Information)

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4.3 Invitro dissolution studies



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Dissolution testing was carried out in USP dissolution apparatus II (paddle type) using

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6.8 pH phosphate buffer at 50 rpm and a temperature of 37±0.5 0C. Aliquots of 3 ml were

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removed at a time interval of 5, 10, 15, 30, 45, 60, 90 and 120 min and replaced with the blank

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phosphate buffer pH 6.8. The amount of the drug released was estimated by UV-Visible

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spectroscopy at a λmax of 276 nm. All the dissolution studies other than plain drug (#sieve no. 44

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pass and 60 retain) were carried out on samples passed through #sieve no. 30 and retained on #

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sieve no.44 (A.S.T.M) fraction.25 Dissolution profile analysis was carried out using DDSolver.26

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Comparisons were drawn based on the percentage of drug released at specific time point (Qt).

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5.0 Results & discussion

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5.1 Selection of solvent system

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Fine and fragile aggregates were formed with ethanol, wherein the aggregation tendency

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with ethanol/water system was less and the system required more amount of bridging liquid for

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the formation of agglomerates. IPA/water formed irregular dense agglomerates and the yield was

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poor. Acetonitrile/water gave platy crystals. Hence, these systems were not considered for

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further studies. Methanol/water and acetone-water showed acceptable morphology as shown in

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figure S1 (Supporting Information) when compared to other solvent systems. Aggregates formed

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with acetone/water were dense, with acceptable yield and less amount of fines; being ICH class

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III solvent was preferred for further processing. In absence of bridging liquid, drug crystallized

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into platy morphology in acetone instead of agglomerates. This confirmed the need for bridging

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liquid to help in the formation of agglomerates. Hence, for all further studies, DCM was used as

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a bridging liquid.

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5.2 Selection of agglomeration region

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Spherical agglomeration technique was used to prepare the spherical crystals. For a batch

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of 1 gm of drug, the agglomeration zone at 45 ml of water, 5 ml of acetone and 1 ml of DCM

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gave best results and was taken forward for further trials. Ternary phase diagrams depicting

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miscible (figure 1A) and immiscible region (figure 1B) are depicted in figure 1. Miscible region

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was further categorized into non-crystallizing zone (figure 1C), pasty zone (figure 1D),

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agglomerating zone (figure 1E) and spherical agglomerating zone (figure 1F).

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5.3 Preparation of spherical agglomerates

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5.3.1 Effect of the stirring speed


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Speed effects formation, size distribution and sphericity of the agglomerates. In spherical

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agglomeration, the spherical morphology is obtained due to optimal mechanical force imparted

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for a specific period during stirring and is one of the main parameter influencing average

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diameters of the agglomerate crystals. Agitation speed mainly affects the crystallization tendency

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and the dispersion of the bridging liquid throughout the system.9 Higher speeds lead to

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production of fines while lower speeds lead to formation of the large and irregular agglomerates.

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From the studies, 700 rpm was found to be optimal for the production of spherical agglomerates.

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Effect of speed on shape of agglomerates is pictorially depicted in figure S2 (Supporting

241

Information).

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Figure 1 Ternary phase diagram of acetone-water-DCM; A) Miscible region; B) Immiscible

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region; C) Non-crystallizing zone; D) Pasty mass; E) Agglomeration zone and F) Spherical

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agglomeration zone (Black spot)

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5.3.2 Effect of the polymers and combinations

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Sphericity plays an important role in flow and dissolution. Presence of large particles or fines

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during compression is usually responsible for issues related to weight variation, hardness and

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drug release. It is hence important to balance these attributes of the agglomerates during process

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optimization. Various attempts were made to develop blends with optimal sphericity, highest

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possible drug release in 15 minutes and efficient yields of sieve #30 - #44 fractions. All the

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discussions henceforth are in connection with results enlisted in table 1.



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5.3.2.1 HPMC

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The types of polymer used and their concentration is a critical factor that must be

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considered during the development of spherical agglomerates. Different grades of HPMC (E3,

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E5 and E15) were explored at 0.1 %, 0.25 % and 0.5 % w/v concentrations. Among them, only

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E3 with 0.1 % concentration gave the better sphericity with an aspect ratio (AR) of 0.87, (Table

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1, figure S3a Supplementary Information) when compared with other grades. Large irregular

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agglomerates were formed even at lower concentrations of E5 and E15 possibly due to high

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viscosity affecting the mobility of the crystals in the crystallization medium. E3 at higher

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concentrations (0.25 % and 0.5 % w/v) also resulted into irregular agglomerates (Table S3,

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figure S3b and S3c Supplementary Information) due to higher viscosity of the crystallization

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medium. Total yield obtained with E3 was 85% out of which the acceptable fraction was only

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66%. Copolymers PEG 400, PVA and Poloxamer (POLOX) at different levels were incorporated

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to improve sphericity, yield and dissolution. Sphericity (AR 0.91) was improved by addition of

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PEG at 5% w/v due to its solubilising and tensioactive properties. It also contributed to enhanced

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dissolution (Q15=49 %). Total yield obtained with (E3+PEG) was around 86% with improved

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usable yield of (90%) fraction when compared to agglomerates prepared with only 0.1% E3. In

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addition, the spheroids were more uniform with less surface irregularity when used with 5 % w/v

270

PEG. However, as the concentration of PEG increased, fines and irregular agglomerates with

271

lower yields were obtained (Table S4, figure S4b and S4c Supplementary Information). PVA

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was also explored at 0.1, 0.25 and 0.5% w/v concentrations to understand its effect on sphericity,

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yield and dissolution. Agglomerates obtained with PVA at 0.1 and 0.25 % have shown an AR of

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0.73 and 0.75 and Q15 of 62 % and 60 % respectively. Sphericity decreased significantly and a

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marginal improvement in dissolution was observed when compared to E3+PEG system. Paste

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was formed at 0.5% w/v of PVA and above. Total yield obtained with 0.1% w/v of PVA was

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although 88 %, a larger proportion was oversized and undersized agglomerates and hence not

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selected for further studies. Addition of POLOX at 0.1%, 0.25% and 0.5% w/v concentrations

279

improved dissolution. As observed with PEG, higher concentrations of POLOX also resulted in

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irregular agglomerates. POLOX at 0.1% w/v resulted in optimal sphericity (AR=0.85) and

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enhanced dissolution (Q15 of 80%). Total useable fraction obtained with E3+POLOX was 70%.

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As the concentration of the POLOX increased, yield retained on #sieve no. 44 increased owing

283

to its surfactant properties (Figure S5d, S5e and S5f Supplementary Information).


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Table 1 Agglomerate yield, sphericity and dissolution of polymers and combinations Polymers and combinations

Total yield

% Fraction retained on sieve (100 % of the total yield ) # 22 #30 - #44 # 60 (Over size) (Useable (under size) fraction) 7.5 66 10 5 85 6 16 62 20

% release in 15 min (Q15)

Aspect ratio (AR)

E3 (0.1%) E3+PEG (0.1/5%) E3+PEG (0.1/10%)

85 86 78

43 49 57

0.87 0.91 0.86

E3+PEG (0.1/15%) E3+HPC (0.1/0.1%) E3+HPC (0.1/0.05%) E3+HPC (0.05/0.05) E3+PVP (0.1/0.1%) E3+PVP (0.1/0.25%)

55 80 83 85 70 Paste

47 6 5 30 10 *

45 85 90 65 49.3 *

8 4 10 5 40.5 *

60 68 70 49 79 *

0.79 0.86 0.84 0.83 0.73 *

E3+PVP (0.1/0.5%) E3+PVA (0.1/0.1%) E3+PVA (0.1/0.25%) E3+PVA (0.1/0.5%) E3+POLOX (0.1/0.1%) E3+POLOX (0.1/0.25%)

Paste 88 76 Paste 70 71

* 22 9.7 * 23 16

* 58 71.42 * 70 71

* 15 13 * 3.4 9.8

* 62 60 * 80 80

* 0.73 0.75 * 0.85 0.83

E3+POLOX (0.1/0.5%) HPC (0.2%) HPC+PEG (5%) HPC+PVA (0.05/0.05%) HPC+POLOX (0.05/0.05%) PVP (0.05%)

78 70 65 72 62 62

14 75 60 70 45 60

83 25 21 19 10 25

3.8 0 15 11 12.5 12

85 37 70 70 82 66

0.73 * * * * *

PVP+PEG (0.05/5%) PVP+POLOX (0.05/0.05%) PVP+PVA (0.05/005%) E3+HPC+PEG 5%

60 65 62 77.5

70 72 76 9.03

21 13 13 84.5

9 10 9 5.2

68 77 80 93

* * * 0.88

E3+HPC+PEG 10% E3+HPC+PEG 15%

85 81

13.46 16.76

40.5 73.52

46 9.7

91 91

0.7 0.67

E3+HPC+POLOX 0.1% E3+HPC+POLOX 0.25% E3+HPC+POLOX 0.5% E3+HPC+PVA 0.1 % E3+HPC+PVA 0.25 % E3+HPC+PVA 0.5 %

70 63 63 86 86 63

21 8 19 9.2 17 44

54.5 53 55.85 48 75.48 63

22 39.6 24.2 42.7 8 2.5

69 87 91 68 63 67

0.89 0.8 0.72 0.8 0.72 0.66

*Unevaluated because of formation of irregular agglomerates, large clumps and pasty mass

286 287 288



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289

Page 12 of 23

5.3.2.2 HPC

290

HPC grades L, M and H were explored at 0.1, 0.25 and 0.5% w/v. Agglomerates formed

291

with HPC L (0.25%) gave agglomerates with acceptable sphericity (AR = 0.92) but 75 % of the

292

yield was retained on the #sieve no. 22 and hence a lower dissolution with Q15 of 41 % due to

293

larger particles. This was attributed to higher viscosity of HPC compared to HPMC. Higher

294

viscosity grades (M and H) gave irregular agglomerates and pastes (Table S3 and Figure S3 m, n

295

and o Supplementary Information). Clumps and paste were formed at all the concentrations when

296

HPC was combined with different copolymers PEG, POLOX and PVA (Table S4 Supplementary

297

Information). Due to its higher sphere forming ability, HPC L at 0.25% was considered for

298

combinations with other polymers.

299

5.3.2.2 PVP

300

Experiments carried out with different concentrations 0.1 %, 0.25 % and 0.5 % w/v of

301

PVP (K17, K25 and K30) resulted in agglomerates with irregular morphology at all

302

concentrations of lower viscosity grade K17, and clumps and pastes with higher viscosity grades

303

K25 and K30. High viscosity grades of all the polymers resulted in irregular agglomerates and

304

clumps owing to their viscosity.27 Results obtained from the screening of polymers are tabulated

305

in table S3 (Supporting Information).

306

5.3.2.3 Polymer combinations (E3+HPC)

307

Presence of HPMC (E3) and HPC was found to have good impact on sphericity, as they

308

are commonly used excipients in extrusion-spheronization along with MCC.28,

309

polymers were combined at 0.1% w/v concentration each, total usable yield obtained was 85%.

310

Oversized fraction retaining on #sieve no. 22 was found to be very less (6%). Combination of

311

polymers (E3+HPC) resulted in spherical agglomerates of plates with rough surface (Figure 3).

312

Agglomerates formed were with optimal sphericity with AR of 0.86 and Q15 of 68%. HPC

313

improved dissolution despite formation of thick plates owing to its de-aggregation tendencies.9

314

Reduction in size of the agglomerates was seen when lower amount of HPC was employed

315

(0.1% of E3 and 0.05% of HPC). E3: HPC (2:1) gave higher yield of 85 % with an optimal

316

sphericity (AR=0.84) and improved dissolution with Q15 of 70 %. E3 acting as stabilizer on the

317

surface of the agglomerates might have hindered the coalescence of the crystals resulting

318

agglomerates with reduced particle size.11

319


29

When both

Page 13 of 23

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

320


5.3.2.3 Polymer-polymer-copolymer combinations

321

This combination of E3+HPC (2:1) ratio was further explored with different copolymers

322

PEG 400 (5 %, 10 %, and 15 %), POLOX (0.1, 0.25 and 0.5 %) and PVA (0.1%, 0.25% and

323

0.5%) to improve sphericity and dissolution. Sphericity was improved in presence of PEG 5%.

324

E3+HPC+PEG has shown better dissolution and improved aspect ratio of 0.91 and Q15 of 94 %.

325

Total yield obtained was 78 % with maximum fraction retained on #sieve no. 44. Agglomerates

326

obtained using this combination was uniform with smooth surface (Figure 2) and optimal drug

327

release, attributed to spheronizing property of HPC with modified viscosity and wetting

328

properties of PEG, leading to uniform distribution of drug in the ternary system.9 Higher

329

concentration of the PEG (10 %, 15 %) formed irregular agglomerates possibly due to higher

330

viscosity.30 E3+HPC with POLOX (0.1 %) gave optimal sphericity (AR of 0.89) and Q15 of 69

331

% and total yield obtained was 70%. Although the oversized fraction was more, this formulation

332

was included for further comparison studies due to its optimal sphericity and improved

333

dissolution. Higher concentration of the POLOX improved dissolution but agglomerates were

334

found to be irregular in shape. No improvement in sphericity and dissolution were observed

335

when PVA was used as copolymer with E3+HPC. Yields were also low compared to other

336

combinations. Higher concentration of PVA (0.5%) resulted into formation of the paste. SEM

337

images of optimized formulations are represented in figure 3; all the formulations are on 500 µm

338

scale except plain drug which is in 100 µm scale.

339

Considering yield, sphericity and dissolution data; formulations encoded E3, E3+PEG,

340

E3+HPC, E3+POLOX, E3+HPC+PEG, and E3+POLOX+HPC were taken up for further

341

characterisation and evaluation.

342



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Page 14 of 23

343 344

Figure 2 SEM images of optimized formulations depicting surface topography and process

345

improvements

346

Observations related to polymer combinations are provided in table S4 and figure S4, S5

347

(Supporting Information). Schematic flow of the polymer optimization and property

348

enhancements are represented in the following flowchart (Figure 3) for easy understanding.


Page 15 of 23

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349 350 351 352 353 354 355

Figure 3 Flow chart describing optimization and selection of polymers for improving various properties. (HPMC and HPC represents optimized low viscosity grades E3 and L respectively SSphericity, D-Dissolution, M-Mechanical strength, NP - Not performed, + Positive scoring of properties, - Irregular agglomerates and pastes, and hence unevaluated)

356

Dissolution profiles of polymer-polymer-copolymer combinations along with controls are

357

represented in figure 4. Dissolution profiles of E3 and copolymer combinations are provided in

358

figure S6 (Supplementary information)



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Page 16 of 23

359 360 361

Figure 4 Dissolution profiles of polymer-polymer-copolymer combinations 5.4 Solid state characterization

362

SEM results are already discussed in section 5.3.2 and are represented in figure 2.

363

Curious case where plates were perfectly agglomerated into spheroids is pictorially depicted in

364

figure 5. Etodolac shows characteristic peaks in IR spectra related to O-H, N-H and C–H

365

stretching modes at 3340 cm-1, 2930 and 3000 cm-1. C=C bond stretching vibration was observed

366

at 1736 cm-1. FT-IR spectra of etodolac and formulations were superimposable. No significant

367

changes in the IR spectra of polymer and etodolac were observed indicating absence of

368

polymorphic changes and incompatibilities. Representative IR spectra are provided in figure S7

369

(Supporting Information). Thermal analysis of drug revealed a melting region of 149-155 0C

370

with a melting point of 150.73 0C. No significant changes in the thermograms were observed

371

except for E3. E3 has shown a split in the endothermic peak in the melting region possibly due to

372

minor transition observed in the excipients (HPMC) in the region 131-157 0C as represented in

373

figure S8 (Supporting Information). Physical mixture also showed similar behaviour as (figure

374

S9 Supporting Information) possibly due to glass transition of E3 in the region 140-160 0C.

375

Representative thermograms of all the formulations along with the thermal data are provided in

376

figure S10 and table S5 (Supporting Information). P-XRD was employed to identify any changes

377

induced by the polymers, solvents or by the process. Characteristic diffraction peaks of etodolac

378

were observed at 2θ values of 13.65°, 14.45°, 16.58°, 17.78°, 18.66°, 19.58, 20.43°, 21.59°,


Page 17 of 23

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379

23.36°, 24.35° and 27.46°. No significant changes were observed in the diffraction patterns of

380

any of the formulations developed (figure S11 Supporting Information). Data from IR, DSC and

381

P-XRD confirms the absence of polymorphic changes and incompatibility in the developed

382

agglomerates.

383 384 385

Figure 5 SEM images of A) E3 B) E3+HPC C) E3+PEG D) E3+POLOX E) E3+HPC+PEG and F) E3+HPC+POLOX depicting agglomeration of plates into spheroids.

386

6.0 Evaluation of pharmaceutical properties

387

6.1 Micromeritics

388

All agglomerates have shown improved micromeritics compared to plain drug. Plain drug

389

has shown poor flow and formulations E3, E3+POLOX, E3+HPC+PEG and E3+HPC+POLOX

390

have shown excellent flow. Comparative analysis of angle of repose, Carr’s index and Hausners

391

ratio are provided in table S6 (Supplementary information).

392

6.2 Compressibility Studies

393

Plain drug has shown capping tendency (Figure 6, 1C). All the formulations have shown

394

improved compressibility with higher hardness at similar pressures operated for compression of

395

plain drug. Hardness values are provided in table S7 (Supplementary information). All the

396

formulations were showing plastic tendency owing to presence of polymers which improved

397

binding.19, 31 These materials bond after viscoelastic deformation and resist change. It is a time

398

dependant phenomenon and bonding strength increases with increase in the dwell time. They are

399

ideal for direct compression at low pressures.4,

32

Polymer-polymer-copolymer combinations



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Page 18 of 23

400

showed slight decrease in hardness compared to polymers alone owing to lower binding

401

capabilities of copolymers.

402 403

Figure 6 Results obtained from compressibility studies 1) Plain drug 2) E3 3) E3+POLOX 4)

404

E3+PEG 5) E3+HPC 6) E3+HPC+PEG 7) E3+HPC+POLOX

405


Page 19 of 23

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406


7.0 Conclusions

407

Spherical agglomerates of etodolac were successfully prepared using various polymers.

408

During recrystallization trials, intriguing phenomenon of agglomeration of platy crystals into

409

spheroids was observed. Modified habits post recrystallization has shown reduced release

410

possibly due to hydrophobic surface groups. Agglomerates were developed with various

411

polymers (HPMC, HPC, and PVP) and polymer-copolymer (PEG, Poloxamer, and PVA)

412

combinations. No agglomeration was observed with all grades of PVP. Low viscosity grades of

413

HPMC and HPC were found to be crucial for agglomeration but were forming hard and irregular

414

agglomerates with reduced drug release at 15 minutes. Sphericity and dissolution was

415

successfully tailored using combination of polymers and copolymers. A unique combination of

416

HPMC-HPC-PEG resulted in spheroids of thin plates with improved flow and dissolution. 94 %

417

of drug release was achieved in 15 minutes. Copolymers decreased hardness of compacts but

418

improved sphericity and dissolution. All solid forms were characterised using SEM, FT-IR,

419

DSC, and P-XRD. All agglomerates have shown improved flow properties when compared to

420

plain drug. Compressibility studies revealed elastic nature of etodolac due to capping tendency

421

despite change in lubrication time and dwell time. All the agglomerates have shown plastic

422

tendencies with improved hardness at low pressures. These blends with improved dissolution and

423

mechanical strength would help in direct compression of rapidly dissolving tablets for

424

application in the treatment of arthritis.

425

Acknowledgements

426

The authors acknowledge financial support from the Department of Pharmaceuticals (DoP),

427

Ministry of Chemicals and Fertilizers, Govt. of India. Prof. Arvind K Bansal, Department of

428

Pharmaceutics, NIPER-Mohali is acknowledged for his support with microscopic studies. We

429

thank Dr. Dinesh Kumar, Solid State Pharmaceutical Cluster, Trinity College, Dublin; for useful

430

discussions and suggestions.

431

Supporting Information

432

This article contains supporting information; table S1 - Qualitative solubility of etodolac in

433

various organic solvents, table S2 - Wells protocol for studying compressibility, table S3 -

434

Screening of the polymers, table S4 - Screening of the copolymers, table S5 - Onset, melting and

435

endset points of agglomerates, table S6 - Flow evaluation of agglomerates, table S7 Hardness



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 23

436

values and inference from compressibility studies, table S8 Drug release and dissolution

437

efficiency at 15 minutes, figure S1 - Agglomerates with different solvent system. A)

438

Methanol/water/DCM; B) Acetonitrile/water/DCM C) Ethanol/water/DCM D) IPA/water/DCM

439

E) Acetone/water/DCM and F) Acetone, figure S2 - Effect of speed of rotation on the

440

agglomerates A) 500 rpm; B) 700 rpm; C) 900 rpm, figure S3 - Agglomerates at different

441

polymer concentrations and different grades of polymers, figure S4 - Microscopic images of E3

442

in combination with different copolymers, figure S5 - Microscopic images of HPC/E3 (2:1)

443

combination with copolymers, Figure S6 Dissolution profiles of E3 and copolymer

444

combinations, figure S7 - IR spectra of plain drug with formulation, figure S8 - DSC

445

thermogram of HPMC E3, figure S9 - DSC thermograms of plain drug along with HPMC E3

446

formulations and physical mixture., figure S10 - DSC thermograms of plain drug with

447

formulations, figure S11 - Overlay of powder diffractograms of formulations. "This material is

448

available free of charge via the Internet at http://pubs.acs.org." at the end.

449 450

Corresponding author *E mail: [email protected]

451

Notes

452

The authors declare no competing financial interest.

453 454

8.0 References

455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472

(1) Patel, S.; Kaushal, A. M.; Bansal, A. K., Compression physics in the formulation development of tablets. Crit Rev Ther Drug Carrier Syst 2006, 23, (1), 1-66. (2) Andersen, H. C., Molecular dynamics simulations at constant pressure and/or temperature. J Chem Phys 1980, 72, (4), 2384. (3) Balata, G.; Shamrool, H., Spherical agglomeration versus solid dispersion as different trials to optimize dissolution and bioactivity of silymarin. J Drug Deliv Sci Technol 2014, 24, (5), 478-485. (4) Aulton, M. E.; Wells, T., Pharmaceutics: The science of dosage form design. 2 ed.; Churchill Livingstone London:: 2002; Vol. 1. (5) Berkovitch-Yellin, Z.; Van Mil, J.; Addadi, L.; Idelson, M.; Lahav, M.; Leiserowitz, L., Crystal morphology engineering by" tailor-made" inhibitors; a new probe to fine intermolecular interactions. J Am Chem Soc 1985, 107, (11), 3111-3122. (6) Bodmeier, R.; Paeratakul, O., Spherical agglomerates of water-insoluble drugs. J Pharm Sci 1989, 78, (11), 964-967. (7) Bolhuis, G.; Zuurman, K.; Te Wierik, G., Improvement of dissolution of poorly soluble drugs by solid deposition on a super disintegrant. II. The choice of super disintegrants and effect of granulation. Eur J Pharm Sci 1997, 5, (2), 63-69. (8) Paradkar, A.; Pawar, A.; Mahadik, K.; Kadam, S., Spherical Crystallisation: A novel particle design technique. Indian Drugs 1994, 31, 229-229.


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(9) Javadzadeh, Y.; Vazifehasl, Z.; Dizaj, S. M.; Mokhtarpour, M., Spherical Crystallization of Drugs. ed.; Intech open: 85-104, 2015. (10) Kawashima, Y.; Cui, F.; Takeuchi, H.; Niwa, T.; Hino, T.; Kiuchi, K., Improved static compression behaviors and tablettabilities of spherically agglomerated crystals produced by the spherical crystallization technique with a two-solvent system. Pharm Res 1995, 12, (7), 1040-1044. (11) Morishima, K.; Kawashima, Y.; Kawashima, Y.; Takeuchi, H.; Niwa, T.; Hino, T., Micromeritic characteristics and agglomeration mechanisms in the spherical crystallization of bucillamine by the spherical agglomeration and the emulsion solvent diffusion methods. Powder Technol 1993, 76, (1), 5764. (12) Paradkar, A.; Pawar, A.; Chordiya, J.; Patil, V.; Ketkar, A., Spherical crystallization of celecoxib. Drug Dev Ind Pharm 2002, 28, (10), 1213-1220. (13) Patra, C. N.; Swain, S.; Mahanty, S.; Panigrahi, K. C., Design and characterization of aceclofenac and paracetamol spherical crystals and their tableting properties. Powder Technol 2015, 274, 446-454. (14) Thakur, A.; Thipparaboina, R.; Kumar, D.; Kodukula, S. G.; Shastri, N. R., Crystal Engineered Albendazole with Improved Dissolution and Material Attributes. CrystEngComm 2016, (9), 1489-1494. (15) Singh, S.; Singh, R.; Kushwah, A. S.; Gupta, G., Neuroprotective role of antioxidant and pyranocarboxylic acid derivative against AlCl3 induced Alzheimer’s disease in rats. J Coast Life Med 2014, 2, (7), 571-578. (16) Glasner, A.; Avraham, R.; Rosenne, E.; Benish, M.; Zmora, O.; Shemer, S.; Meiboom, H.; BenEliyahu, S., Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a β-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol 2010, 184, (5), 2449-2457. (17) Carson, D. A.; Leoni, L. M.; Corr, M. P., Use of etodolac to treat hyperplasia. In ed.; Google Patents: 2007. (18) Carson, D. A.; Cottam, H. B.; Adachi, S.; Leoni, L. M., Use of etodolac in the treatment of multiple myeloma. In ed.; Google Patents: 2006. (19) Kumar, S.; Chawla, G.; Bansal, A. K., Spherical crystallization of mebendazole to improve processability. Pharm Dev Technol 2008, 13, (6), 559-568. (20) Viswanathan, C. L.; Kulkarni, S. K.; Kolwankar, D. R., Spherical agglomeration of mefenamic acid and nabumetone to improve micromeritics and solubility: A technical note. AAPS PharmSciTech 2006, 7, (2), E122-E125. (21) Kenji, M.; Yoshiaki, K.; Hirofumi, T.; Toshiyuki, N.; Tomoaki, H.; Yoichi, K., Tabletting properties of Bucillamine agglomerates prepared by the spherical crystallization technique. Int J Pharm 1994, 105, (1), 11-18. (22) Wilhelm, K.-P.; Maibach, H. I., OECD guidelines for testing of chemicals. Dermatoxicology, 7th edn. CRC Press, Boca Raton 2008, 303-305. (23) Guideline, I. H. T., Impurities: guideline for residual solvents Q3C (R3). Current Step 2005, 4. (24) Shah, R. B.; Tawakkul, M. A.; Khan, M. A., Comparative evaluation of flow for pharmaceutical powders and granules. AAPS Pharmscitech 2008, 9, (1), 250-258. (25) Ibrahim, M. M.; Mohamed, E.-N.; El-Setouhy, D. A.; Fadlalla, M. A., Polymeric surfactant based etodolac chewable tablets: Formulation and in vivo evaluation. AAPS PharmSciTech 2010, 11, (4), 17301737. (26) Zhang, Y.; Huo, M.; Zhou, J.; Zou, A.; Li, W.; Yao, C.; Xie, S., DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. The AAPS journal 2010, 12, (3), 263-271. (27) Raghavan, S.; Trividic, A.; Davis, A.; Hadgraft, J., Crystallization of hydrocortisone acetate: influence of polymers. Int J Pharm 2001, 212, (2), 213-221. (28) Mangal, H.; Kirsolak, M.; Kleinebudde, P., Roll compaction/dry granulation: Suitability of different binders. Int J Pharm 2016, 503, (1), 213-219.



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(29) Nokhodchi, A.; Maghsoodi, M.; Hassan-Zadeh, D.; Barzegar-Jalali, M., Preparation of agglomerated crystals for improving flowability and compactibility of poorly flowable and compactible drugs and excipients. Powder Technol 2007, 175, (2), 73-81. (30) Kawashima, Y.; Handa, T.; Takeuchi, H.; Okumura, M.; Katou, H.; Nagata, O., Crystal modification of phenytoin with polyethylene glycol for improving mechanical strength, dissolution rate and bioavailability by a spherical crystallization technique. Chem Pharm Bull 1986, 34, (8), 3376-3383. (31) Ebube, N. K.; Hikal, A. H.; Wyandt, C. M.; Beer, D. C.; Miller, L. G.; Jones, A. B., Effect of drug, formulation and process variables on granulation and compaction characteristics of heterogeneous matrices. Part 1: HPMC and HPC systems. Int J Pharm 1997, 156, (1), 49-57. (32) Aulton, M. E.; Taylor, K. M., Aulton's pharmaceutics: the design and manufacture of medicines. 4th ed.; Elsevier Health Sciences: 2013.

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For Table of Contents Use Only

534


535

Supriya Jitkar, Rajesh Thipparaboina, Rahul B Chavan, Nalini R Shastri*

536 537


538

Graphical Abstract

539 540

A curious observation showcasing agglomeration of platy crystals into spheroids is presented for

541

the first time. This research presents a systematic flow of events in spherical crystallization

542

deploying various polymers HPMC, HPC, PVP and copolymers PEG, PVA and Poloxamer. A


Page 23 of 23

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543

unique combination of HPMC-HPC-PEG resulted in spheroids of thin plates with improved flow

544

and dissolution, yielding blends suitable for direct compression with higher hardness at lower

545

pressures.

546


Spherical Agglomeration of Platy Crystals: Curious Case of Etodolac

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