Improving the dissolution rate of a poorly water-soluble drug via adsorption onto pharmaceutical diluents

Accepted Manuscript Improving the dissolution rate of a poorly water-soluble drug via adsorption onto pharmaceutical diluents Hien Van Nguyen, Chulhun Park, Euichaul Oh, Beom-Jin Lee PII:

S1773-2247(16)30135-6

DOI:

10.1016/j.jddst.2016.05.008

Reference:

JDDST 211

To appear in:

Journal of Drug Delivery Science and Technology

Received Date: 6 April 2016 Revised Date:

2 May 2016

Accepted Date: 2 May 2016

Please cite this article as: H. Van Nguyen, C. Park, E. Oh, B.-J. Lee, Improving the dissolution rate of a poorly water-soluble drug via adsorption onto pharmaceutical diluents, Journal of Drug Delivery Science and Technology (2016), doi: 10.1016/j.jddst.2016.05.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Graphical abstract

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Improving the dissolution rate of a poorly water-soluble drug via adsorption onto pharmaceutical diluents Hien Van Nguyen a,1, Chulhun Park a,1, Euichaul Ohc and Beom-Jin Leea,b,*

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College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea

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Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Republic of Korea

College of Pharmacy, The Catholic University, Bucheon 420-743, Republic of Korea

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E-mail address: [email protected] (B.-J. Lee). Equally contributed

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∗ Corresponding author: Tel.: +82 31 219 3442; fax: +82 31 212 3653.

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Abstract 20

The purpose of this study was to improve the dissolution rate of poorly water-soluble

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celecoxib (CXB) via a new adsorption method. CXB was dissolved in a co-solvent (ethanol:dichloromethane = 40:60 v/v) and then adsorbed on the surface of various diluent carriers by wet grinding. The physicochemical properties, such as the morphology and crystal structure, of the resulting adsorption powders were characterized. The adsorption powders were

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compressed into tablets after the wet granulation process. The in vitro dissolution rate of the

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CXB-loaded tablet was assessed in intestinal fluid (pH 6.8) containing 1% sodium lauryl sulfate. The differential scanning calorimetry and powder X-ray diffraction data showed that the crystallinity of CXB was maintained in the adsorption powders. Fourier transform infrared 30

spectra indicated a molecular hydrogen-bonding between CXB and the adsorption carriers.

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Lactose monohydrate was the most effective at improving the dissolution rate of CXB via strong hydrogen bonding, followed by mannitol, Avicel® PH102, A-tab®, and Di-tab®. The CXB-loaded tablet was also stable during storage conditions (ambient: 25°C, 60% RH, accelerated: 40°C,

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75% RH). Adsorption of CXB onto a hydrophilic diluent carrier provides an effective pharmaceutical strategy to enhance the dissolution rate of CXB-loaded tablets without changing

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drug crystallinity.

Keywords: poorly water-soluble drug; adsorption method; pharmaceutical diluents; enhanced dissolution rate; drug crystallinity; hydrogen bonding 40

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1.

Introduction

Poorly water-soluble drugs formulation is one of the major current challenges in pharmaceutical industry. It has been reported that about 40% of oral immediate release formulations currently on the market contain poorly water-soluble drugs [1-3]. Poor solubility

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leads to low bioavailability, particularly for biopharmaceutical classification system (BCS) class II drugs, whose bioavailability is limited by their dissolution rate.

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Celecoxib (CXB), a non-steroidal anti-inflammatory drug, is a specific cyclooxygenase-2 inhibitor used for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain [4-6], and has also been proved to lead to a better outcome in cancer treatment when used in combination

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with chemotherapeutic agents compared to chemotherapeutic agents alone [7]. However, CXB is a BCS II drug and has extremely low solubility in hydrophilic media [8, 9]; its chemical structure is presented in Fig. 1. The solubility of crystalline CXB is approximately 3–7 µg/mL in water.

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With a pKa of 11.1, the solubility of CXB is unaffected by pH over the physiologically relevant range of pH values [10]. Regarding the pharmacokinetic properties of CXB, the bioavailability is around 40%, the half-life is 11 h, protein binding is 97%, hepatic metabolism is mainly by

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CYP2C9, and excretion is via the renal (27%) and fecal (57%) routes [11]. Several formulation approaches have been investigated to improve the solubility and

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dissolution rate of CXB, thus improving the bioavailability. For instance, particle size reduction [12, 13], solid dispersion [14-16], β-cyclodextrin complexation [17, 18], nanosuspension [19], and co-crystal techniques [20] have been previously utilized to solubilize CXB. However, these techniques have been limited in terms of the unsatisfactory dissolution rate, low physicochemical stability and the manufacturing complexity of CXB-loaded formulations. Herein, a new adsorption method was developed to enhance the dissolution rate of CXB

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without changing drug crystallinity and good stability during storage conditions. This is accomplished by dissolving the drug in an organic solvent and then adsorbing this solution onto the carrier. The evaporation of the organic solvent results in the rapid precipitation of the drug on

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the surface of the adsorbent materials [21]. This is a simple and time-saving method that increases drug dissolution properties by reducing the drug particle size, thus improving the 70

surface area of the drug available for contact with the dissolution medium. According to the

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Noyes–Whitney equation, when the surface area increases, the dissolution rate is in turn enhanced [22].

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In this work, we found a new type of carrier and solvent system, which have never been used previously for enhanced dissolution of CXB via adsorption method. Various pharmaceutical 75

diluents were investigated to adsorb model drug in a small quantity and newly found that lactosebased adsorbent system is very effective to be prepared and easy to design oral CXB tablet.

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Pharmaceutical diluents used as adsorption carriers included lactose monohydrate, mannitol, Avicel® PH 102, A-tab®, and Di-tab®. Their chemical structures are shown in Fig. 1. Our new adsorption systems have novelties as compared with conventional ones. Firstly, as compared to solid dispersion in terms of preparation process, adsorption method is different from

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solvent-based solid dispersion method. In solid dispersion, both the drug and carrier were

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dissolved or dispersed in solvent, then this solvent was removed by drying process using spray drying or freeze drying [23]. Therefore, the amount of solvent used for making solid dispersion is typically large. In contrast, for our adsorption method, only drug was dissolved in optimally 85

selected solvent and then the drug solution was adsorbed on the carriers by simple wet grinding. In other words, the carrier was not dissolved or dispersed in solvent. As a result, the amount of solvent used is much smaller than that of solid dispersion [21, 24]. Secondly, unlike micronized

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drugs, which are more likely to agglomerate due to their hydrophobicity, thus reducing their available surface area [25, 26], the adsorption method reduces the tendency to agglomerate. 90

Hence, the increased dissolution rate achieved by the adsorption method is maintained during

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manufacturing process and storage. Finally, our system could be effectively applied a poorly water-soluble drug with high does strength like CXB (200 mg). Conventionally, common adsorbents such as fumed silica and crosslinked polyvinylpyrrolidone have been used with a

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large amount for adsorption studies but these systems are almost ineffective to be swallowed due to the large size of tablet and also induce stability problems [21].

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Various physicochemical and molecular interactions were then characterized to elucidate the pharmaceutical mechanisms. The crystal structures of drug in adsorption mixture were characterized by using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The morphology and particle size were also determined by using scanning electron microscopy (SEM). The molecular interaction between the drug and the carrier was examined by

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using Fourier transform infrared (FTIR) spectroscopy.

2.1. Materials

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2. Materials and methods

CXB was purchased from Aarti Drugs Limited (Mumbai, India). Lactose monohydrate and mannitol were obtained from DFE Pharma (Tokyo, Japan). Microcrystalline cellulose (Avicel®PH102) was purchased from FMC (Philadelphia, USA). Dicalcium phosphate anhydrous (A-tab®) and dicalcium phosphate dihydrate (Di-tab®) were purchased form Whawon 110

Pharm Ltd. (Seoul, Korea). Polyvinylpyrrolidone K30 (PVP K30) was obtained from BASF

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Chemicals (New Jersey, USA). Sodium lauryl sulfate (SLS) was purchased from Sigma-Aldrich (Missouri, USA). All other chemicals were of analytical grade. Water was purified by reverse

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osmosis.

2.2. Determination of celecoxib solubility

An excess amount of CXB was added to conical flasks containing 30 mL of various media,

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including distilled water, absolute ethanol, dichloromethane and cosolvent, pH 1.2, pH 6.8, pH 7.4, pH 6.8 with SLS (0.2%, 0.4%, 0.6%, 0.8% and 1%). The resulting samples were sonicated

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for 15 minutes then shaken in a shaking water bath (BS-06, JEIO Tech, Seoul, Korea) for 48 hours at 37 °C (150 rpm). The contents of each conical flask were filtered through a 0.45-µm filter; the filtrate was subsequently diluted with media and then analyzed using high-performance liquid chromatography (HPLC). The solubility studies were carried out in triplicate.

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2.3. Preparation of celecoxib adsorption mixture The adsorption mixture was prepared by wet grinding. First, CXB (30 g) was dissolved in the

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co-solvent of absolute ethanol:dichloromethane (60:40 v/v) (120 mL) until a clear solution was obtained. The resulting solution was added gradually to the adsorption carrier (30 g) in

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combination with grinding using a pestle and mortar. Finally, the mixture was dried in an oven at 60 °C for 2 hours. The detailed mechanism to show drug adsorption onto pharmaceutical diluents 130

is clearly illustrated in Fig. 2.

2.4. Tablet formulations CXB tablets were prepared by wet granulation method with the tablet compositions presented in Table 3. Except for F0 (physical mixture-based), all the formulations used an adsorption 6

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mixtures of CXB and diluent (lactose monohydrate, mannitol, Avicel® PH102, A-tab® and Ditab®) to enhance the dissolution rate of CXB. Firstly, CXB and diluent in the form of an adsorption mixture or a physical mixture were passed through a 0.5-mm sieve, and were then

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mixed with croscarmellose sodium. The resulting mixture was then kneaded with a polyvinylpyrrolidone K30 binder solution with a suitable amount of water. In case of F6 140

formulation, SLS was then added to this mixture. The damp mass was passed through a 1-mm

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sieve, then dried in a conventional oven at 60 °C for 2 hours, and then sifted through a 0.8-mm sieve. The resultant granules were compressed using a rotary tablet press machine (Rotary Tablet

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2.5. Differential scanning calorimetry

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Press RT-8, DCM Korea) equipped with flat-faced punches (10 mm).

DSC thermograms of pure CXB and the adsorption mixture of CXB–lactose monohydrate

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were obtained by scanning from 30–300 °C at 10 °C/min with a differential scanning calorimeter (Netzsch, DSC 200 F3, Germany). Nitrogen was used as the purge gas. Each sample (approximately 5mg) was weighed in a standard open aluminum pan using an empty pan as a reference.

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2.6. Powder X-ray diffraction

The PXRD patterns of the pure drug, lactose monohydrate, the physical mixture, the adsorption mixtures of CXB and the adsorbents were obtained using a high-resolution X-ray 155

diffractometer (Pigaku, Ultima III, Japan). The samples were scanned in 0.02° steps from 20° to 60° (diffraction angle 2θ) at 40 kV with150 mA Cu-Kα radiation.

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2.7. Fourier transform infrared All the samples that were characterized by PXRD were also investigated by FTIR 160

spectrophotometer (Agilent, California, USA). The wavelength set from 500 to 4000 cm−1 was

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recorded with a resolution of 2 cm−1.

2.8. Scanning electron microscopy

Tokyo, Japan) at 5 kV. Each sample was mounted onto a carbon tape and coated with platinum for 2 minutes in air.

2.9. Dissolution rate studies

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The sample surface morphologies were characterized by using SEM (JEOL, JMS-6700F,

The in vitro dissolution rate of the dosage forms was determined in triplicate with dissolution tester (D-TWELVE, DCM, Korea) in intestinal fluid (pH 6.8) containing 1% SLS at 37 °C at a

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rotation speed of 50 rpm according to the United States Pharmacopeia (USP) Apparatus II paddle method. At 5, 15, 30, 45 and 60 minutes, samples were withdrawn and replaced with an equal

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volume of fresh dissolution media. The withdrawn aliquot was immediately filtered through a 0.45-µm membrane (regenerated cellulose). The drug concentration was then determined by HPLC.

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2.10 . Stability studies

The optimized tablet dosage form containing adsorption mixture and commercial reference capsule Celebrex® were subjected to stability studies. The samples were stored in the plastic 180

bottles together with desiccants (silica gel pack). The stability studies were carried out in 2

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conditions, which are ambient condition (25°C , 60% RH) and accelerated condition (40°C , 75% RH) in a constant temperature and humidity chamber (DA-HCT-300, DONGA Scientific Corp., Seoul, Korea) for 6 months. At each pre-determined time points (initial, 1 month, 3 months, 6

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months), 9 tablets (or capsules) from each sample were removed and evaluated for appearance, drug content (n=3), related substance (n=3) and dissolution profiles in medium pH 6.8 buffer containing SLS 1% (n=3). The content of CXB and its degraded substances were investigated by

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2.11. HPLC analysis

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HPLC at a wavelength of 254 nm.

The CXB concentration in the solution was determined using HPLC (Waters Corp., Massachusetts, USA) with a Gemini 5µm C18 110A analytical column (150×4.6mm) (Phenomenex, California, USA). A mobile phase of methanol and phosphate buffer (80:20 v/v)

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was used at a flow rate of 1 mL/min. The phosphate buffer was composed of sodium phosphate monohydrate dihydrate (NaH2PO4.2H2O, 3.1 g) and triethylamine (10 mL) in 1000 mL of 195

distilled water, which was adjusted to pH 3.0 using diluted phosphoric acid. The UV detector

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was set at 254nm to analyze the column effluent. The entire solution was filtered through a 0.45µm membrane filter (Millipore Corp., Bedford, USA) and was degassed prior to use. Samples (5

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µL) were injected into the HPLC system for analysis.

3. Results and discussion

3.1. Drug solubility The solubility of CXB in various physiological media and organic solvents was tested. In

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general, CXB exhibited very low solubility in all physiological media, including pH 1.2, pH 6.8, pH 7.4, and distilled water as shown in Table 1, which is in accordance with the results of some previous studies [19, 27]. Furthermore, there was no significant difference in the solubility of

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CXB in different media over the pH range from 1.2 to 7.4, which proves that the solubility of CXB is not dependent on pH. Therefore, pH-based solubilization methods are unlikely to 210

enhance the solubility of CXB or its dissolution rate. In addition, a solubility test was carried out

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with intestinal fluid (pH 6.8) containing various concentrations of SLS to select an appropriate dissolution medium to use in the dissolution test. When operating under sink conditions, the

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paddle apparatus should contain a volume of dissolution media that is at least three times the saturation volume. According to the solubility results, it can be concluded that the solubility of 215

CXB is drastically increased when SLS is added to pH 6.8 medium. However, even if 1% SLS is added, it is still not sufficient to obtain sink conditions for dissolution test of 200 mg CXB

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dosage forms. In this study, intestinal fluid (pH 6.8) containing SLS 1%, which is a non-sink condition medium, was chosen as the dissolution test medium. In the adsorption method, CXB has to be dissolved in solvent before being adsorbed onto the surface of the carrier. For this reason, the solubility of CXB in different organic solvents and co-

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solvents was also investigated to determine the best solvent to use for dissolving CXB. The data

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in Table 2 showed that the binary solvent consisting of absolute ethanol and dichloromethane (60:40 v/v) is the most suitable solvent for this purpose.

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3.2. In vitro dissolution studies Dissolution studies for CXB are very challenging because of the extremely low solubility of CXB in physiological conditions. Dissolution test was performed with the marketed product

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Celebrex® and all test formulations. The medium used in these studies was intestinal fluid (pH 6.8) containing SLS 1%. 230

Dissolution profiles of adsorbed celecoxib to illustrate the impact of carrier types and the

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effectiveness of the adsorption method and the synergistic effect of SLS are given in Fig. 3. To be more specific, among the adsorption carriers, lactose monohydrate exhibited the best improvement in the CXB dissolution rate, followed by mannitol, Avicel® PH102, dicalcium

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phosphate anhydrous granular (A-tab®), and dicalcium phosphate dihydrate granular (Di-tab®). It is worth noting that the water-soluble adsorption carriers showed better enhancement than that of

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the water insoluble ones. This is due to the fact that water-soluble adsorbents, such as lactose monohydrate and mannitol have many polar hydroxyl (O-H) groups whose hydrogen atoms can easily interact with the hydrogen-receiving agents (-NH2, -SO2, -F) of CXB, resulting in the formation of intermolecular hydrogen bonds. The stronger the hydrogen bond between CXB and the adsorption carrier, the smaller the particle size of CXB. This CXB–adsorbent interaction

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prevents CXB from recrystallizing, keeping the particle size small so that it can be attached onto the carrier. Moreover, the dissolution rate of the F1 formulation, which uses lactose monohydrate

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as the adsorption carrier, is equivalent to that of commercial capsules Celebrex®. Therefore, the adsorption method for crystalline CXB (CXB particle size is over 200 µm) can provide dissolution enhancement comparable to Celebrex® using micronized CXB and solubilizer.There

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was a dramatic improvement when the adsorption method was applied. The CXB dissolution rate showed an eight-fold increase from 10% for the F0 control tablet having physical mixture of CXB and lactose monohydrate to 81.4% for the F1 adsorption-applied tablet after 60 minutes of dissolution testing. 250

Regarding the role of the solubilizer, when SLS (2% w/w of the tablet total weight) was added

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in formulation (F6), the dissolution rate was significantly increased, reaching approximately 100% drug release within 30 minutes. In conclusion, the reduced particle size (provided by the adsorption method) and the solubilizer are two effective factors for CXB dissolution

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enhancement. In case of BCS class II model drug such as CXB, the bioavailability is proportional to the enhanced dissolution rate although no bioavailability study is carried out [13, 28]. However, pharmacokinetic studies are under investigation in rats to prove the improvement

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3.3. Differential scanning calorimetry

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of oral CXB bioavailability when adsorption method is applied.

The DSC thermograms of pure CXB and the adsorption mixture of CXB–lactose monohydrate are shown in Fig. 4. The DSC curve of pure CXB exhibited a single endothermic peak at 165 °C, which relates to the intrinsic melting point of CXB. The endothermic peak for the adsorption

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mixture shifted to 162.1 °C, indicating the drug–adsorbent interaction. The enthalpy of the peak for the adsorption mixture was also much smaller than that of the pure drug (15.5 J/g compared 265

to 104.3 J/g). Thus, it can be concluded that the crystallinity of CXB is maintained when it is

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bound onto the surface of lactose monohydrate.

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3.4. Powder X-ray diffraction

The PXRD diffractograms of CXB, lactose monohydrate, the physical mixture, and the 270

adsorption mixture are presented in Fig. 5. As can be clearly seen from the PXRD spectra, there were no significant differences between the PXRD spectra of pure CXB, the physical mixture, and the adsorption mixture. The physical mixture and the adsorption mixture still reveal peaks characteristic of crystalline CXB, which shows that CXB remained in the crystalline state after

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being adsorbed onto the adsorbent with reduced particle size. 275

3.5. Fourier transform infrared

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FTIR spectra (Fig. 6) were obtained to investigate the molecular interactions between the functional groups of CXB and the adsorption carrier (mainly lactose monohydrate). The bands for pure CXB at 3336.4 and 3230.0 cm-1 correspond to the N-H stretching in the SO2NH2 group, and 1346.3 and 1163.6 cm-1 to the S=O asymmetric and symmetric stretching. The lactose

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monohydrate band corresponding to the hydroxyl group (O-H) is a very broad peak at 3200–

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3300 cm-1. In the FTIR spectrum of the adsorption mixture, it is apparent that the wide peak of the hydroxyl group of lactose monohydrate drastically diminishes in intensity, and two CXB bands from the N-H group also diminish and shift to lower wavelengths (3334.1 and 3329.4 cm285

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O-H group of lactose monohydrate, possibly by hydrogen bond formation (Fig. 7). In contrast, the hydroxyl group (O-H) band remains almost unchanged in the physical mixture, which hides two sharp peaks corresponding to the N-H group of CXB. Therefore, FTIR analysis confirmed

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that stronger hydrogen bonds were formed between the drug and the carrier in the adsorption mixture compared to the corresponding physical mixture. This result can be used to explain the

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significant reduction of the drug particle size when the adsorption method is applied.

3.6. Scanning electron microscopy The scanning electron micrographs for pure CXB, lactose monohydrate, and the physical and 295

adsorption mixtures of CXB and lactose monohydrate are presented in Fig. 8. The micrographs help elucidate the structure of the adsorption mixture, in which needle-shaped crystalline CXB is

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attached onto the surface of lactose monohydrate as the adsorbent material. Furthermore, it can be clearly seen that, by adsorbing CXB on lactose monohydrate, the particle size of CXB is dramatically reduced from over 200 µm to just under 20 µm, leading to dissolution rate enhancement for CXB. The pictures of all the other adsorption mixtures using mannitol, Avicel®

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PH102, A-tab®, and Di-tab® as adsorbents were similar (data not shown).

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3.7. Stability studies

The stability data of optimized CXB tablet formulation (F6) and commercial reference capsule, celebrex® in ambient (25 °C, 60% RH) and accelerated (40 °C, 75% RH) conditions

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were shown in Table 4 and Table 5, respectively. In general, physical and chemical stability of CXB were characterized by appearance, drug content and related substances test. As can be clearly seen, those properties of both CXB tablet sample and reference capsule remained

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unchanged over the period of 6 months during two storage conditions. This is attributed to the good stability properties of CXB in different temperatures and humidities. Furthermore, the dissolution profiles of both sample and reference formulations also showed no significant

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reduction during 6 months of stability testing. It can be concluded that the crystallinity and particle size of CXB in absorption mixture were unchanged so that a good dissolution profiles of

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CXB tablet samples were maintained even when subjected to accelerated conditions. Additionally, the drug in adsorption mixtures existed in crystalline form based on aforementioned DSC and PXRD data, while the morphology of the drugs in solid dispersion is usually amorphous, suggesting that adsorption mixture is more stable than solid dispersion [29, 30].

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4.

Conclusion

An increased CXB dissolution rate was achieved via new adsorption method with

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pharmaceutical diluents. DSC, PXRD, and SEM data indicated that the CXB particle size was significantly reduced and there was no change in the crystal structure of CXB in the adsorption 325

mixtures. Among the adsorption carriers tested, lactose monohydrate showed the greatest

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dissolution rate of CXB via strong hydrogen bonding. Furthermore, when SLS was added to the formulation (F6) in combination with the adsorption method, a synergistic effect to enhance the

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dissolution rate of CXB was obtained. The current adsorption process of CXB with hydrophilic diluent carrier provides an effective way to enhance the dissolution rate by forming 330

intermolecular hydrogen bonding and reducing particle size without changing drug crystallinity.

Acknowledgements

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This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Ministry of Science, ICT & Future Planning, 2013 Patient-centric R&D Project (2013M3A9B5075841), Korea

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to the biopharmaceutics classification system, International journal of pharmaceutics, 321 (2006)

[23] C.L.-N. Vo, C. Park, B.-J. Lee, Current trends and future perspectives of solid dispersions containing

poorly

water-soluble

European

Journal

of

Pharmaceutics

and

TE D

Biopharmaceutics, 85 (2013) 799-813.

drugs,

[24] P. Nkansah, A. Antipas, Y. Lu, M. Varma, C. Rotter, B. Rago, A. El-Kattan, G. Taylor, M. Rubio, J. Litchfield, Development and evaluation of novel solid nanodispersion system for oral delivery of poorly water-soluble drugs, Journal of Controlled Release, 169 (2013) 150-161.

EP

405

[25] N. Rasenack, B.W. Müller, Micron-size drug particles: common and novel micronization

AC C

techniques, Pharmaceutical development and technology, 9 (2004) 1-13. [26] P. Khadka, J. Ro, H. Kim, I. Kim, J.T. Kim, H. Kim, J.M. Cho, G. Yun, J. Lee, Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and 410

bioavailability, asian journal of pharmaceutical sciences, 9 (2014) 304-316. [27] G. Chawla, P. Gupta, R. Thilagavathi, A.K. Chakraborti, A.K. Bansal, Characterization of solid-state forms of celecoxib, European journal of pharmaceutical sciences, 20 (2003) 305-317.

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[28] Y. Kawabata, K. Wada, M. Nakatani, S. Yamada, S. Onoue, Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: Basic approaches and 415

practical applications, International Journal of Pharmaceutics, 420 (2011) 1-10.

Advanced drug delivery reviews, 48 (2001) 27-42.

RI PT

[29] L. Yu, Amorphous pharmaceutical solids: preparation, characterization and stabilization,

Pharmacy and Pharmacology, 61 (2009) 1571-1586.

AC C

EP

TE D

M AN U

420

SC

[30] S. Janssens, G. Van den Mooter, Review: physical chemistry of solid dispersions, Journal of

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Table 1

Saturation solubility (µg/mL)

pH 1.2

4.20

pH 6.8

5.20

Distilled Water

4.95

pH 7.4

13.35

pH 6.8 + SLS 0.2%

76.11

pH 6.8 + SLS 0.4%

180.60

pH 6.8 + SLS 0.6%

282.12

pH 6.8 + SLS 0.8%

419.02

M AN U

TE D

pH 6.8 + SLS 1%

SC

Media

RI PT

Solubility of celecoxib in media with different pH and SLS concentrations

519.00

EP

SLS: Sodium lauryl sulfate

AC C

425

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430

Table 2

RI PT

Solubility of celecoxib in different organic solvents and co-solvents

Saturation solubility (mg/mL)

Methanol

113.94

Absolute ethanol

83.35

Dichloromethane

50.00

Absolute ethanol:dichloromethane (25:75v/v)

166.67

Absolute ethanol:dichloromethane (60:40 v/v)

250.00

Absolute ethanol:dichloromethane (50:50 v/v)

171.50

Absolute ethanol:dichloromethane (75:25 v/v)

111.11

EP AC C

435

TE D

M AN U

SC

Organic solvent

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Table 3 The formulation compositions (milligrams) of the investigated celecoxib-loaded tablets F1b 200 200 -

F2b 200 200 -

F3b 200 200

-

-

-

-

23.0 22.5 4.5

23.0 22.5 4.5

23.0 22.5 4.5

Total weight

450

450

450

F5b 200 -

F6b 200 200 -

200

-

-

23.0 22.5 4.5

23.0 22.5 4.5

200 23.0 22.5 4.5

14.0 22.5 9.0 4.5

450

450

450

450

M AN U

a

F4b 200 -

RI PT

F0a 200 200 -

SC

Formulation Celecoxib Lactose monohydrate Mannitol Avicel PH102 Dicalcium phosphate anhydrous granular (A-tab®) Dicalcium phosphate dihydrate granular (Di-tab®) Polyvinylpyrrolidone K30 Croscarmellose sodium Sodium lauryl sulfate Magnesium stearate

Control tablet formulation (celecoxib and the carrier were physically mixed) Adsorption-applied tablet formulation (celecoxib was adsorbed onto the carrier to make the adsorption

b

EP

TE D

mixture)

AC C

440

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445

RI PT

Table 4

expressed as mean ± standard deviation (n=3).

Dissolution rate (%), pH 6.8 + 1% SLS 15 min 30 min 60 min Assay (%) Appearance (good or not)

EP

Dissolution rate (%), pH 6.8 + 1% SLS 15 min 30 min 60 min Assay (%)

450

AC C

Accelerated (40 °C, 75% RH)

Initial

1 month

M AN U

Ambient (25 °C, 60% RH)

Evaluations Appearance (good or not)

3 months

6 months

good

good

good

good

65.5 ± 3.7 96.0 ± 1.7 101.6 ± 0.9

74.8 ± 5.2 99.4 ± 1.3 103.2 ± 2.6

77.1 ± 11.2 99.6 ± 1.1 101.1 ± 0.3

56.1 ± 6.7 82.5 ± 1.8 95.7 ± 2.2

101.2 ± 1.0

101.0 ± 0.3

101.7 ± 1.4

102.5 ± 0.3

good

good

good

good

65.5 ± 3.7 96.0 ± 1.7 101.6 ± 0.9

75.9 ± 10.8 97.9 ± 2.2 100.5 ± 1.7

66.9 ± 7.7 96.8 ± 0.5 99.4 ± 0.6

52.7 ± 0.6 82.7 ± 0.7 97.2 ± 2.4

101.2 ± 1.0

101.0 ± 0.9

100.9 ± 1.5

101.9 ± 0.1

TE D

Storage condition

SC

Stability profiles of optimized celecoxib tablet formulation (F6) in ambient and accelerated conditions. The reported values are

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Table 5

Ambient (25 °C, 60% RH)

Evaluations Appearance (good or not)

Initial good

Dissolution rate (%), pH 6.8 + 1% SLS 15 min 30 min 60 min

3 months

6 months

good

good

good

72.0 ± 13.0 80.4 ± 12.5 85.0 ± 10.0

65.1 ± 5.7 76.0 ± 0.8 83.3 ± 1.6

45.2 ± 5.3 63.0 ± 14.7 72.7 ± 12.3

57.6 ± 10.7 74.5 ± 9.1 82.8 ± 4.2

103.3 ± 0.5

103.5 ± 0.6

102.0 ± 1.4

105.1 ± 0.1

good

good

good

good

Dissolution rate (%), pH 6.8 + 1% SLS 15 min 30 min 60 min

72.0 ± 13.0 80.4 ± 12.5 85.0 ± 10.0

54.1 ± 21.1 75.7 ± 3.0 82.9 ± 1.2

54.8 ± 9.0 74.1 ± 7.8 78.6 ± 8.3

31.7 ± 16.1 56.6 ± 6.5 70.9 ± 5.9

Assay (%)

103.3 ± 0.5

103.0 ± 0.3

103.1 ± 1.3

105.5 ± 0.2

EP

Appearance (good or not)

TE D

Assay (%)

Accelerated (40 °C, 75% RH)

1 month

M AN U

Storage condition

SC

expressed as mean ± standard deviation (n=3).

AC C

455

RI PT

Stability profiles of commercial reference capsule, celebrex® in ambient and accelerated conditions. The reported values are

24

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Figure List 460

RI PT

Fig. 1. Molecular structure of (a) celecoxib, (b) lactose monohydrate, (c) mannitol, (d) microcrystalline cellulose Avicel® PH102, (e) dicalcium phosphate anhydrous granular (A-tab®),

465

SC

and (f) dicalcium phosphate dihydrate granular (Di-tab®).

Fig. 2. Schematic representation of the protocol adopted for the preparation of adsorption

M AN U

mixture.

Fig. 3. Dissolution profiles of adsorbed celecoxib. Top: Effect of different diluents: lactose monohydrate (F1), mannitol (F2), Avicel® PH102 (F3), A-tab®(F4), Di-tab® (F5); Bottom: Comparison of dissolution profile with control tablet (F0), adsorption-applied tablet (F1) and

TE D

470

SLS-added tablet (F6). SLS: sodium lauryl sulfate.

EP

Fig. 4. Differential scanning calorimetry thermograms of pure celecoxib and the adsorption

475

AC C

mixture of celecoxib-lactose monohydrate.

Fig. 5. Powder X-ray diffraction patterns. From the bottom: pure celecoxib, lactose monohydrate, celecoxib-lactose monohydrate physical mixture, and celecoxib–lactose monohydrate adsorption mixture.

480

25

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Fig. 6. Fourier transform infrared spectra. From the top: pure celecoxib, lactose monohydrate, celecoxib–lactose monohydrate physical mixture, and celecoxib–lactose monohydrate adsorption

RI PT

mixture. 485

Fig. 7. Schematic representation of hydrogen bonding between celecoxib and lactose

SC

monohydrate.

monohydrate (B), celecoxib-lactose monohydrate physical mixture (C), celecoxib-lactose

EP

TE D

monohydrate adsorption mixture (D) at two magnifications (×100, ×1000).

AC C

490

M AN U

Fig. 8. Scanning electron microscopy photomicrographs of pure celecoxib (A), lactose

26

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(a)

TE D

(b)

M AN U

SC

RI PT

495

(e)

EP

(d)

AC C

500

Fig. 1. 505

27

(c)

(f)

M AN U

SC

RI PT

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Fig. 2.

AC C

515

EP

TE D

510

28

ACCEPTED MANUSCRIPT

100 90

F1

80

F3

RI PT

Drug release (%)

F2 70 60 50

F4

40

F5

SC

30

Celebrex® commercial reference drug

20

0 0

10

20

30

M AN U

10

40

50

60

Time (min)

TE D

80

60

40

F0

F1

F6

EP

Drug release (%)

100

AC C

20

0

0

520

525

10

20

30

40

Time (min)

Fig. 3.

29

50

60

ACCEPTED MANUSCRIPT

530

RI PT

2

1

SC

-1

-2

-3

-4

-5 0

50

100

M AN U

DSC (mW/mg)

0

150

200

250

300

TE D

Temperature (°C)

535

AC C

Fig. 4.

EP

Pure CXB Adsorption mixture of CXB and lactose monohydrate

30

350

ACCEPTED MANUSCRIPT

0

10

20

M AN U

SC

RI PT

540

30

40

2θ

545

AC C

Fig. 5.

EP

TE D

Pure CXB Lactose monohydrate CXB-lactose monohydrate physical mixture CXB-lactose monohydrate adsorption mixture

31

50

4000

3000

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

2000

Wavenumber (1/cm)

1000

TE D

Adsorption mixture of CXB and lactose monohydrate Physical mixture of CXB and lactose monohydrate Lactose monohydrate Pure CXB

EP

550

555

AC C

Fig. 6.

32

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R O

O

R

RI PT

H H H

O N

R

S H

O

H

SC

O N

H O

F

N

C

R

M AN U

F

H

F

R

H

O

TE D

H3C

Hydrogen bond O

H Lactose monohydrate

EP

R

AC C

560

Fig. 7.

33

O

R

ACCEPTED MANUSCRIPT

565

×100

RI PT

×1000

(A)

M AN U

SC

570

(B)

EP

(C)

TE D

575

AC C

580

(D)

585

590

Fig. 8. 34