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Preparation and characterization of solid dispersions of celecoxib obtained by spray-drying ethanolic suspensions containing PVP-K30 or isomalt
Journal of Drug Delivery Science and Technology 46 (2018) 188–196
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Preparation and characterization of solid dispersions of celecoxib obtained by spray-drying ethanolic suspensions containing PVP-K30 or isomalt
T
Saeed Motallae, Azade Taheri, Alireza Homayouni∗ Department of Pharmaceutics, School of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
A R T I C LE I N FO
A B S T R A C T
Keywords: Celecoxib Isomalt PVP Solid dispersion Spray drying
Celecoxib (CLX) is an anti-inflammatory drug that is used for acute pain treatment, but it has very low oral bioavailability owing to its poor water solubility. In this study, CLX solid dispersions are prepared by spraydrying using hydrophilic carriers with the aim of improving its apparent solubility and dissolution rate. Blends with different ratios of CLX, isomalt (ISO) and PVP were prepared in ethanol, and solid dispersions were obtained using a spray dryer. The saturation solubility and dissolution kinetics in 0.25% SLS and 0.04 M Na3PO4 containing media were determined. Also, SEM, DSC, XRPD, and stability studies were used to characterize the systems. Physicochemical analysis demonstrated the presence of amorphous CLX in the spray dried samples. The saturation solubility and dissolution rate of CLX from these formulations were higher than those for pure celecoxib and its physical mixtures. Amorphous CLX showed a lower dissolution rate compared to its crystalline form in 0.25% SLS medium, while this tendency was reversed under alkaline conditions. The CLX:PVP:ISO 3:5:2 spray dried sample showed the highest dissolution rate in both media. Exposure of samples to high moisture (75% humidity) recrystallized some of the amorphous CLX. Thus, the results showed that the dissolution rate of CLX was enhanced in 0.25% SLS, whereas a reduction in dissolution rate was observed in 0.04 M Na3PO4.
1. Introduction Celecoxib (CLX) is a nonsteroidal anti-inflammatory drug (NSAID) that is used for the treatment of acute pain, such as osteoarthritis, rheumatoid arthritis, and dysmenorrhea. However, its poor water solubility (1–3 μg/ml) restricts its oral bioavailability to about 30% [1]. According to the biopharmaceutical classification system (BCS), CLX can be categorized as a Class II drug (poorly water soluble and high gastrointestinal permeability). In this class, dissolution is the rate-limiting step for absorption from the gastrointestinal tract; thus, with increasing solubility and dissolution rate, the oral bioavailability of these drugs improves [2]. Moreover, celecoxib, with needle-like crystalline shape, suffers from poor pharmaceutical properties, particularly unfavorable compressibility and poor flowability [3]. These conditions create various problems with the preparation of a solid dosage form in the pharmaceutical industry. Thus, it is important to improve the physicochemical and physicomechanical properties of celecoxib to enhance its solubility and flowability. Various strategies have been used to improve the poor water solubility of hydrophobic drugs. For example, making solid dispersions [4,5], reducing the particle size [6,7], cocrystallization [8], and the cyclodextrins [9] have been used before in recent years to improve the
∗
solubility and dissolution behavior of these drugs. Among these techniques, preparation of solid dispersion formulations of the active pharmaceutical ingredient (API) is one of the most favorable strategies owing to its simple and cost-effective method of preparation. In these systems, the API is simply dispersed in a non-pharmacological and safe carrier. The carrier must have good hydrophilic properties so that it can dissolve in water and hydrate the hydrophobic API [5]. Typically, polymers are used as carriers so the solid-state matrix and the API are usually amorphous. In these conditions, the drug in amorphous form exhibits a higher dissolution rate owing to its weaker lattice structure compared to in its crystalline state [4]. Moreover, in solid dispersion systems, a reduction in the drug's particle size (sometimes to the molecular level) can lead to enhancement of the dissolution rate and oral bioavailability of poorly water-soluble drugs. Melting and solvent evaporation are the most common methods used for the preparation of solid dispersion formulations. In the solvent evaporation technique, the API and carrier are simply dissolved in a common solvent, and then the solvent is evaporated to obtain a solid dispersion of the drug and carrier [5]. Spray drying is an effective technology for the preparation of solid dispersions. In this method, fast solvent evaporation leads to rapid transformation of the API–carrier solution to a solid API–carrier matrix [10].
Corresponding author. E-mail addresses: [email protected], [email protected] (A. Homayouni).
https://doi.org/10.1016/j.jddst.2018.05.020 Received 31 January 2018; Received in revised form 13 May 2018; Accepted 13 May 2018 Available online 15 May 2018 1773-2247/ © 2018 Elsevier B.V. All rights reserved.
Journal of Drug Delivery Science and Technology 46 (2018) 188–196
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Table 1 Spray-drying yield and theoretical vs. actual percent drug loading of solid dispersions. Solid dispersions
Yield of spray dryer(%)
Theoretical drug loading(%)
Actual drug loading(%)
Saturation solubility (μg/ml)
Raw CLX CLX SD CLX:ISO 7:3 SD CLX:ISO 5:5 SD CLX:ISO 3:7 SD CLX:ISO 1:9 SD CLX:PVP:ISO 3:5:2 CLX:PVP:ISO 3:2:5 CLX:ISO 7:3 PM CLX:ISO 5:5 PM CLX:ISO 3:7 PM CLX:ISO 1:9 PM CLX:PVP:ISO 3:5:2 CLX:PVP:ISO 3:2:5
_ _ 30.1 49.2 50.3 53.7 52.6 51.5 _ _ _ _ _ _
_ _ 70 50 30 10 30 30 _ _ _ _ _ _
_ _ 66.9 ± 0.4 41.5 ± 0.5 24.1 ± 0.5 5.8 ± 0.3 19.7 ± 0.3 25.8 ± 0.1 _ _ _ _ _ _
0.96 1.10 1.97 3.11 2.75 3.28 5.41 3.87 1.92 1.66 1.86 1.78 2.69 2.14
SD SD
PM PM
± ± ± ± ± ±
1.5 1.2 2.5 1.5 2.5 2.1
± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.02 0.05 0.07 0.13 0.04 0.14 0.20 0.11 0.06 0.07 0.10 0.02 0.08 0.14
spray drying was performed with the following conditions: inlet temperature 105 °C, outlet temperature 60 °C, suspension flow rate of about 5 mL/min, and N2 atomized flow rate of 35 m3/h. The spray-dried particles were stored in closed vials until needed for further studies.
Several formulation approaches have been used before to improve the solubility and dissolution behavior of CLX. Preparation of CLX solid dispersions in PVP, HPMC, PVA, PEG, poloxamer 188, Soluplus®, and Kollicoat® has been reported before [11–17]. PVP K30 has been used to produce homogenous, stable, amorphous solid dispersions of CLX and reduce the particle size to the molecular level, thus making this polymer a promising carrier for solid dispersion formulations of CLX [11,13,18]. Beside the good performance of PVP as a hydrophilic carrier for enhancing the dissolution of CLX, sugar alcohols such as isomalt (ISO) could provide appropriate physicochemical properties for solid dosage forms. ISO, which has half the sweetening potency of sugar but similar taste, is used as a sweetener in the food and pharmaceutical industries. This sugar does not decompose in the mouth and does not decay teeth, so it is a good alternative to sucrose for use in the food and pharmaceutical industries. In addition, ISO can be used as a filler and binder in tablets, especially in oral disintegration tablets (ODTs), owing to its good mechanical properties [19–21]. Moreover, the large number of hydroxyl groups in its structure and high water solubility of this sugar make ISO a suitable carrier for solid dispersion formulations [22]. In this study, the effects of different ratios of PVP K30 and isomalt (Galen IQ 810) in CLX solid dispersions obtained from alcoholic suspensions were investigated. In addition, the effects of moisture on the physicochemical properties of the solid dispersions after 1 month of storage were demonstrated.
2.2.2. Preparation of physical mixtures of drug/Carrier (PM) The physical mixtures of CLX, ISO, and PVP-K30 with the same ratios as those used in the spray drying method were prepared by mixing the sieved fractions (smaller than 250 μm) of compounds using mortar and pestle. 2.2.3. Determination of spray-drying yield and drug loading The yields of the spray-dried samples were calculated by dividing the weight of the recovered particles by the total solid content of CLX and carrier(s) used in the ethanolic suspension. For determination of the drug loading, an accurately weighed amount of each solid dispersion formulation was dissolved an appropriate amount of hydroethanolic solution (70% ethanol in this case) and the concentration of CLX was determined spectrophotometrically based on a calibration curve obtained for CLX at 253 nm wavelength. Preliminary studies showed that the UV absorption of PVP and ISO did not show any interference with CLX at 253 nm. 2.2.4. Scanning electron microscope (SEM) The morphologies of pure CLX, pure ISO, and the spray-dried samples were examined at magnifications of 1000 × and 2000 × using a scanning electron microscope (Philips X series, Netherlands) at an acceleration voltage of 20 kV. Samples were coated with a thin gold–palladium layer by sputter coater (SC 7620, England).
2. Materials and methods 2.1. Materials Celecoxib was purchased from Arastoo Pharmaceutical chemical Inc. (Iran). PVP-K30 was purchased from Sigma-Aldrich (Germany), sodium lauryl sulfate (SLS) was obtained from Merck (Germany), and isomalt (Galen IQ 810) was kindly donated by Beneo Palatinit (Germany). All other solvents and chemicals were of analytical grade.
2.2.5. Determination of saturation solubility Saturated solubility tests were performed on pure CLX as well as the solid dispersion formulations and their physical mixtures. An excess amount of each sample (equivalent to 2 mg of CLX) was added to 10 mL of double-distilled water in a 25 mL, beaker which was sealed with Parafilm® and was shaken at 200 rpm in an air bath (25 °C) for 48 h. After 48 h, the resulting suspensions were filtered through a 0.22-μm cellulose acetate filter (Biofil MCE membrane). The concentration of CLX was determined spectrophotometrically at 253 nm (UV spectrophotometer, Shimadzu, Japan). The solubility of each sample was determined in triplicate and the results reported as means and standard deviations.
2.2. Methods 2.2.1. Preparation of CLX:ISO:PVP solid dispersions via spray drying (SD) Accurate amounts of different ratios of CLX and ISO (7:3, 5:5, 3:7, 1:9) and CLX, ISO and PVP (3:5:2, 3:2:5) were weighed. The aforementioned ratios of celecoxib and isomalt were dispersed in a specific amount of 96% ethanol since celecoxib is soluble in ethanol. However, isomalt is insoluble in ethanol, so a specific type of isomalt (Galen IQ 810) with a small particle size (mean particle size: 22 μm) was used in order to prevent blocking of the spray dryer nozzle. The spray drying operation was performed using a B290 mini spray dryer with a B-295 inert loop (Büchi Labortechnik AG, Flawil, Switzerland). Appropriate mass ratios were prepared from 2% w/v ethanolic suspensions. The
2.2.6. Differential scanning calorimetry (DSC) Differential scanning calorimetry (DSC) studies were performed using a DSC 822e (Mettler Toledo, Switzerland) equipped with a refrigerator cooling system. Samples of the physical mixtures and spraydried formulations (2–3 mg) were placed in aluminum pans sealed with 189
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Fig. 1. SEM image of (A) pure celecoxib, (B) isomalt, (C) CLX:ISO 7:3 SD, (D) CLX:ISO 5:5 SD, (E) CLX:ISO 3:7 SD, (F) CLX:ISO 1:9 SD, (G) CLX:PVP:ISO 3:2:5 SD, (H) CLX:PVP:ISO 3:5:2 SD.
2.2.8. Dissolution studies In order to monitor the dissolution profiles of the prepared CLX formulations, two different dissolution media were used with the USP Apparatus 2 dissolution test (paddle method).
a lid. The crimped aluminum pans were placed inside the DSC and were scanned from 20 to 200 °C at a scanning rate of 10 °C/min under nitrogen gas at a flow rate of 80 mL/min. Melting points and endothermic enthalpies were calculated using the software provided with the instrument (STARe Ver. 12.00 Mettler Toledo, Switzerland).
i For the first dissolution medium, each vessel was filled with 1000 mL of distilled water containing 0.25% w/v Sodium lauryl sulfate (SLS) equilibrated to 37 °C and the paddles were rotated at 50 rpm (as used in our previous studies) [18,23,24]. ii In order to maintain the sink conditions during the dissolution process, the US FDA has approved alkaline medium for the
2.2.7. X-ray powder diffraction studies (XRPD) X-ray powder diffraction (XRPD) measurements were carried out on selected samples using a D8 Advance diffractometer (Bruker, Germany) with Cu Kα radiation (λ = 1.54 Å). Each sample was scanned in the range of 5–80° (2Ɵ) with a step size of 0.05. 190
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dissolution profile of the spray-dried samples, they were stored at 75% humidity (prepared with saturated NaCl solution) and 25 °C for 1 month. After the storage, dissolution tests and XRPD analyses were performed. The dissolution profiles were compared by calculating the similarity factor (f2) using the following equation:
⎧⎡ 1 f2 = 50 log ⎢1 + ⎨ n ⎩⎣
n
−0.5
∑ (Rt − Tt )2⎤⎥ t=1
⎦
⎫ × 100 ⎬ ⎭
(3)
Where n is the sampling number and Rt and Tt are the percentage of dissolved at time point t from the reference and test samples, respectively. If the f2 value is between 50 and 100, the dissolution profiles of the two samples are considered to be equivalent [25]. 3. Results 3.1. Determination of spray-drying yield and drug loading
Fig. 2. DSC trace of raw CLX and spray dried (SD) sample.
The spray-drying yield and drug loading are presented in Table 1. The percentage yield varied between 30% and 53% depending on the ratios of the carriers. An increase in the carrier ratio resulted in an increased yield of celecoxib in the drug product. As shown in Table 1, the actual drug loading is always lower than the theoretical drug loading; however, as the celecoxib ratio decreases, the difference between the actual drug loading and theoretical loading increases.
Table 2 Melting points and enthalpies of fusion for samples prepared by spray drying. N/D = not defined. Peak 1
CLX CLX:ISO 7:3 CLX:ISO 5:5 CLX:ISO 3:7 CLX:ISO 1:9 CLX:ISO:PVP 3:5:2 CLX:ISO:PVP 3:2:5
Peak 2
Peak 3
°C
ΔH (J/g)
°C
ΔH (J/g)
°C
ΔH (J/g)
– 98.56 98.64 97.69 101.88 98.72 –
– 0.82 1.05 3.29 6.62 0.89 –
– 151.93 152.07 152.57 154.56 151.94 –
– 5.05 7.85 33.68 38.25 4.65 –
162.24 162.05 161.94 161.68 160.79 – –
99.83 56.72 33.30 16.31 N/D – –
3.2. Scanning electron microscope (SEM) results SEM was used to investigate the effect of the spray-drying process on the morphology of the obtained samples. SEM images of pure CLX, ISO, and the spray-dried samples are shown in Fig. 1. Pure celecoxib crystals exhibited rod-shape morphology (Fig. 1A) while the ISO particles have an irregular shape and a particle size of approximately 20 μm (Fig. 1B). In the spray-dried samples containing ISO (Fig. 1C, D, E and F), the celecoxib particles presented as needle-shaped crystals on the surface of the ISO particles while in the samples containing PVP, the obtained particles were spherical with almost smooth surfaces (Fig. 1G and H). On increasing the PVP ratio in these samples, this property becomes more pronounced.
dissolution of celecoxib capsules. Therefore, for the second dissolution medium, each vessel was filled with 1000 mL of tribasic sodium phosphate (0.04 M; pH = 12) equilibrated to 37 °C and the paddles were rotated at 50 rpm [24]. An accurate weight of the samples equivalent to 40 mg of CLX powder was placed at the top of the dissolution medium. 5-mL Samples were withdrawn from the vessels, replaced with fresh dissolution medium, and immediately filtered through 0.22-μm cellulose acetate filters (Biofil MCE membrane). The concentration of CLX was determined spectrophotometrically at 253 nm (Shimadzu, Japan) based on a calibration curve obtained for CLX at this wavelength. The dissolution of each sample was carried out in triplicate. PVP and ISO showed no absorption at 253 nm. The dissolution efficiency (DE) and mean dissolution time (MDT) were calculated to reflect the dissolution performance of the prepared CLX formulations. DE is defined as the area under the dissolution curve (y) up to a certain time t, expressed as a percentage of the area of the rectangle described by 100% dissolution in the same time [25]. It is calculated as follows:
DE% =
t ∫0 y.dt
y100.t
× 10
3.3. Determination of saturation solubility The saturation solubility levels for pure CLX, the physical mixtures, and the solid dispersions are reported in Table 1. The saturation solubility of all the prepared samples was significantly increased in comparison to that of pure CLX (P value < 0.05). There was no significant difference between the solubility of the untreated CLX and the spraydried CLX (P > 0.05). The saturation solubility of the CLX:PVP:ISO 3:5:2 SD sample is 5.4 μg/mL, which is about six times greater than the solubility of the pure drug. 3.4. Results of DSC study The DSC thermograms of pure CLX and selected samples are shown in Fig. 2. Pure CLX exhibited a sharp endothermic peak at around 162 °C, which was attributed to its melting point and is in agreement with previously published data [3]. As shown in Fig. 2, all the obtained samples have a small endothermic peak at around 90–100 °C while the enthalpy of the first peaks increases with increasing ISO ratio. In addition to the first peak, the CLX:ISO samples exhibited two peaks close to each other at around 150 °C (2nd peak) and 162 °C (3rd peak). Increasing the ISO ratio in these samples resulted in an enhancement of the enthalpy of fusion for the second peak and a reduction in the enthalpy of fusion for the third peak. In the samples containing PVP, the intensity of the peaks has decreased substantially such that for the CLX:PVP:ISO 3:5:2 sample the peaks have almost completely
(1)
MDT is calculated using the following equations. −
MDT = ∑ ti . ΔMi ∑ ΔMi
− ti = (ti + ti + 1 ) 2
ΔMi = (Mi + 1 − Mi ) (2)
t i is the midpoint of the time period during which the fraction Where − ΔM of the drug is released from the sample. 2.2.9. Stability test In order to investigate the effect of moisture on the solid state and 191
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Fig. 3. XRD pattern of CLX, ISO and selected samples.
3.5. XRPD results
accelerated the dissolution rate of almost all the samples. This enhancement is more pronounced in the SD samples. Moreover, samples containing PVP show higher dissolution rates compared to those of the other samples. According to Table 3, the CLX:PVP:ISO 3:5:2 SD sample exhibited the highest DE60% and the lowest MDT. The key result is the lower DE60% and higher MDT of the CLX SD samples compared to those for raw CLX.
Fig. 3 shows the XRPD patterns for selected samples. Pure CLX exhibited sharp characteristic peaks at 5, 10.5, 15, and 21.53 angle, which indicate the crystalline nature of CLX [3]. PVP-K30 does not exhibit any obvious peaks owing to its amorphous nature, but ISO shows different distinct peaks related to its crystalline structure [24]. The physical mixture samples (CLX:ISO 1:9 PM and CLX:ISO:PVP 3:5:2 PM) have sharp peaks relating to CLX and ISO that are still visible, although their intensity has decreased slightly. However, in the samples prepared by spray drying, the intensity of these peaks has substantially decreased. This result is more pronounced in samples containing PVP.
3.6.2. Dissolution studies in Na3PO4 (0.04 M, pH 12) This medium has been defined by US FDA previously due to maintenance sink condition. As shown in Fig. 4C and D, similar results were obtained for the SD and PM samples. Similar to the first medium, samples containing higher amounts of carrier showed higher dissolution rates. However, this enhancement is more pronounced owing to the sink conditions in Na3PO4 medium. Interestingly, in this medium spray-dried CLX without any additive (CLX SD) presented a higher dissolution rate than that obtained for pure CLX.
3.6. Dissolution study results
3.7. Stability test results
In order to investigate the dissolution profiles of the CLX formulations, two different dissolution media were used.
Recrystallization of the amorphous drug is the biggest problem with solid dispersion formulations. The amorphous drug in these formulation has a greater tendency to recrystallize in the presence of humidity during storage [4]. In this study, XRPD patterns and dissolution behavior of SD samples were investigated after 1 month of storage at a
disappeared. Table 2 shows the changes in the enthalpy of fusion related to various samples prepared by spray drying. In these samples, with increasing ISO ratio the enthalpy of peak 3 (related to CLX) decreases while the enthalpy of peak 2 (related to ISO) increases.
3.6.1. Dissolution studies in 0.25% SLS As shown in Fig. 4, it is clear that the presence of ISO and PVP-K30 192
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Fig. 4. Dissolution profile of pure CLX and Physical mixture (PM) samples in SLS 0.25%(A), pure CLX and spray drying (SD) samples in SLS 0.25% (B) pure CLX and PM samples in Na3PO4 0.04 M(C) pure CLX and SD samples in Na3PO4 0.04 M (D). Table 3 Dissolution efficiency (DE) and mean dissolution time (MDT) in different media of raw CLX and the samples prepared with physical mixtures (PM) or spray-drying (SD) process and also similarity factor (f2) of SD samples after 1 month storage (75% humidity and 25 °C). Sample name
DE% in 0.25% SLS
MDT in 0.25% SLS (min)
DE% in Na3PO4
MDT in Na3PO4 (min)
f2 in 0.25% SLS
f2 in Na3PO4
Raw CLX CLX SD CLX:ISO 7:3 PM CLX:ISO 5:5 PM CLX:ISO 3:7 PM CLX:ISO 1:9 PM CLX: PVP:ISO 3:2:5 CLX: PVP:ISO 3:5:2 CLX:ISO 7:3 SD CLX:ISO 5:5 SD CLX:ISO 3:7 SD CLX:ISO 1:9 SD CLX: PVP:ISO 3:2:5 CLX: PVP:ISO 3:5:2
21.86 13.02 52.01 28.67 31.74 44.02 42.11 48.67 43.75 46.17 51.91 44.02 73.86 77.04
24.25 ± 0.81 26.94 ± 0.43 9.35 ± 0.35 10.49 ± 1.48 7.03 ± 0.32 4.82 ± 0.91 13.59 ± 0.12 13.21 ± 0.92 10.71 ± 0.67 8.53 ± 0.78 16.06 ± 0.29 4.82 ± 0.8 2.9 ± 0.42 1.07 ± 0.23
52.05 59.04 43.32 52.74 54.12 58.04 59.53 63.54 65.41 79.71 75.75 87.03 93.05 94.45
23.32 ± 0.91 21.60 ± 0.58 15.94 ± 0.59 14.9 ± 0.11 14.1 ± 0.58 17.61 ± 0.49 21.22 ± 0.38 19.53 ± 0.42 17.24 ± 0.61 6.13 ± 0.89 13.79 ± 0.53 12.57 ± 0.52 2.93 ± 0.63 3.22 ± 0.19
– – – – – – – – 41.82 44.51 42.53 41.83 53.90 56.74
– – – – – – – – 32.97 37.84 33.56 41.63 72.11 58.54
PM PM
SD SD
± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.91 0.52 0.62 0.47 0.31 0.63 0.25 0.61 0.55 0.43 0.33 0.63 0.93 0.35
± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.55 0.91 0.36 0.61 0.12 0.87 0.71 0.88 0.65 0.83 0.26 0.61 0.53 0.43
significantly, but the dissolution rate for the samples without PVP decreased. For example, more than 60% of the drug was released after 10 min in the freshly prepared sample of CLX:ISO 7:3 SD while after 1 month of storage the amount of drug released after 10 min had reduced to 40%.
humidity of 75% and a temperature of 25 °C. The XRPD patterns and dissolution profiles of selected samples before and after storage are shown in Figs. 5 and 6. As shown in Fig. 5, the characteristic peaks of CLX are not present in the freshly prepared SD samples. However, after storage a slight increase in the intensity of the characteristic CLX peaks could be observed in for the CLX:ISO 1:1 SD and CLX:ISO 1:9 SD samples. This increase was not observed for the samples containing PVP. The results from the dissolution tests after 1 month of storage are presented in Fig. 6. As shown in Fig. 6A, after storage the dissolution rate increased slightly for samples containing ISO without PVP. For example, in the freshly prepared CLX:ISO 1:9 SD sample, about 30% of the drug was released after 5 min while after 1 month of storage, about 45% of the drug was released in the same timeframe. However, in all the samples containing PVP, the dissolution rate did not change significantly. The results for the dissolution tests carried out in 0.04M Na3PO4 after 1 month of storage are shown in Fig. 6B. As shown in the figure, the dissolution rate in samples containing PVP did not change
4. Discussion As shown in Table 1, the percentage yield varied between 30% and 53% depending on the ratio of the carriers. On increasing the carrier ratio (PVP or ISO), the yield increased. This phenomenon is attributed to the presence of ISO. In samples with a high ratio of ISO, the solid content in the suspension is increased. Ethanol 96% was used for spray drying, but ISO does not dissolve completely in ethanol so the micronized particles of ISO became trapped in the collector of the spray dryer while the CLX molecule (which dissolves in ethanol) must be arrangement from its molecular size and forms fine particles. Obviously, during this bottom-up process, the fine particles of CLX are generated alongside the micronized particles, which could escape from the collector 193
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samples, especially in the formulations containing PVP, CLX and PVP generated matrices containing molecular dispersions of CLX and PVP in their structures, which does not occur in the PM samples. The XRPD and DSC results have clearly shown the amorphous state of CLX in these matrices. As mentioned before, in addition to its melting point, pure ISO shows a small broad endothermic peak at around 100 °C, which is attributed to the evaporation of water during heating. The grade of ISO (Galen IQ 810) used in this work contains about 3% water according to the manufacturer (Beneo Palatinit, Germany). As shown in Fig. 2, as the ISO ratio increases, this peak becomes more pronounced. The second peak at around 150 °C is attributed to the melting point of ISO and the third peak is attributed to the melting point of CLX. Since the ratios of ISO are different in the different SD samples, this difference is presented as an enthalpy of fusion in Table 2. Moreover, in the CLX:ISO 1:9 SD sample these two peaks overlapped, which could be caused by the interaction of CLX and ISO during heating or the dissolution of a small amount of ISO in ethanol and its subsequent dispersion with CLX molecules during the spray-drying process. In samples containing PVP, the intensity of all the peaks was decreased, with the CLX:PVP:ISO 3:5:2 SD sample showing no peaks. These results indicated the presence of CLX and ISO in an amorphous state. It has been shown before that CLX and PVP can generate amorphous solid dispersions after spray drying from ethanolic solution [18]. Similar results were obtained from the XRPD studies. As mentioned in the results section, SD samples exhibited lower peak intensities compared to the respective PM samples. For example, in the samples containing PVP (specifically in CLX:PVP:ISO 3:5:2 SD), almost all the characteristic peaks of CLX were diminished. The halo pattern from the XRPD analysis exhibited that the majority of this sample exists in the amorphous state. The amorphous nature of the SD samples could be attributed to the amorphous nature of PVP itself and the fast crystallization of CLX during spray drying. These results are in good agreement with those from DSC studies. Generally, PVP-K30 and ISO (owing to their hydrophilic characteristics) increased the saturation solubility and dissolution rate of CLX in the solid dispersion samples (Fig. 4). As PVP is a hydrophilic polymer, it surrounds the surface of hydrophobic drugs, which, in turn, makes the surface of hydrophobic drug particles more hydrophilic, hence enhancing the wettability of the drug particles for improved dissolution. Moreover, in the SD samples containing PVP, the CLX molecules were present in the amorphous state and amorphous solid dispersion matrices were produced. It has been proved in several previous studies that amorphous solid dispersion systems exhibit higher saturation solubility compared to those for pure drugs or their physical mixtures. These results are more pronounced when the drug participates in hydrogen bonding with the carrier(s) [4,5,18]. As shown in Fig. 4, the lower dissolution rate of CLX SD compared to pure CLX (crystalline form) in 0.25% SLS is noteworthy. This result is converse to that obtained in alkaline medium (0.04 M Na3PO4). Similar results have been reported before by Ghanavati et al. [24]. This phenomenon could be attributed to the devitrification of amorphous CLX in the dissolution medium, as described before for other drugs [27–29]. However, under alkaline conditions, the spray-dried CLX exhibited a higher dissolution rate. As we described in a previous study, amorphous CLX could participate in intermolecular hydrogen bonding, but this hydrogen bonding could break down under alkaline conditions (by power of OH); however, this event does not happen when these samples are introduced to 0.25% SLS dissolution medium. As mentioned before, in samples containing high levels of carrier, such as CLX:PVP:ISO 3:5:2 SD, the dissolution rate is higher than all of other samples (Fig. 4B and D). Although CLX is present in the amorphous state in these samples, in this case, CLX participates in hydrogen bonding with PVP and forms a uniform solid dispersion matrix. This state accelerates the hydration of CLX molecules owing to the hydrophilicity of PVP and ISO, hence the observed enhancement of the dissolution rate. Moreover, in these
Fig. 5. XRPD pattern of some prepared samples using spray dryer before and after 1-month storage in 75% humidity and 25 °C temperature.
and become trapped in the outlet filter. Therefore, the yield from spray drying is higher when the ratio of ISO is higher than that of CLX. This justification also explains the lower amount of actual drug loading obtained versus the theoretical drug loading, as presented in Table 1. Regarding Table 1, the actual drug loading of CLX in the CLX:ISO 1:9 SD sample is about 50% of its theoretical drug loading, while in samples with higher ratios of CLX this difference is not seen. The percentage yield and actual drug loading in the samples containing PVP are favorable. The presence of PVP increased the viscosity of the suspension so the production of particles that can settle in the collector, and hence the yield from the spray dryer, have increased. The desirable properties of PVP for the spray-drying process have been demonstrated before in numerous studies [10,18]. As shown in Fig. 1, for the spray-dried samples containing ISO (Fig. 1C, D, E, and F), celecoxib particles (with needle-like crystalline shape) covered the ISO particles. This morphology could be attributed to the fast evaporation of ethanol during spray drying. In this case, before spray drying the suspended ISO particles are surrounded with dissolved CLX in ethanol, so after rapid evaporation of the ethanol, CLX molecules cover the ISO particles. However, after a while, CLX molecules recrystallized to crystalline form and exhibited a needle-like crystal form. In the samples containing both PVP and ISO, the presence of PVP resulted in spherical and uniform particles. It seems that PVP K30 is able to create spherical particles because of its solubility in ethanol and inhibiting the crystal growth of CLX during crystallization (solvent evaporation in the spray-drying process). The effect of PVP as a crystal growth inhibitor has been proved for CLX [11,12] and other drugs before [10,26]. Table 1 shows that the SD samples exhibited higher saturation solubility compared to that of pure CLX (P < 0.05). In addition, all of the SD samples exhibited significant solubility enhancement compared to the respective PM samples (P < 0.05), except for CLX:ISO 7:3. These results could be owing to the different physicochemical characteristics of these samples. In the SD samples, CLX is dissolved in ethanol and is converted to an amorphous state after spray drying. Moreover, in these
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Fig. 6. Dissolution profile of spray dried samples in SLS 0.25% medium (A) and in Na3PO4 0.04 M medium (B) after 1-month storage in 75% humidity and 25 °C temperature.
to its crystalline form; therefore, the conversion of a portion of the amorphous CLX to its crystalline state (during storage in humid conditions) caused a higher dissolution rate compared to the freshly prepared amorphous CLX. The reverse was seen in Na3PO4 medium.
samples, CLX has been dispersed molecularly in the PVP/ISO matrix. In 0.25% SLS, the dissolution enhancement for samples containing more than 50% carrier is obvious. For example, in the CLX:PVP:ISO 3:5:2 SD sample, after 5 min almost 90% of the drug was released while the release of pure CLX did not even reach 40% after 60 min (Fig. 4B). Generally, it is obvious that the CLX dissolution has been enhanced in almost all of the SD samples (Fig. 4), although in Na3PO4 medium the dissolution rate was affected more significantly. This result is attributed to the better dissolution of CLX in alkaline media because of the sink conditions. According to XRPD results (Fig. 5), it is clear that the samples without PVP have recrystallized after 1 month of storage at 75% humidity (CLX:ISO 1:1 and 1:9). However, the amorphous state of CLX was retained in the solid dispersion samples containing PVP. It seems that PVP was able to protect the drug from recrystallization in these samples (Fig. 5). It has been demonstrated before that in solid dispersion formulations the use of a carrier with a high glass transition temperature (Tg) can increase the Tg of the solid dispersion system and protect the amorphous state of the drug from recrystallization [30]. Analysis of dissolution behavior in 0.25% SLS medium showed an increase in the dissolution rate of CLX after 1 month of storage, while the dissolution rate of CLX was decreased in Na3PO4 medium after 1 month of storage (Fig. 6). This phenomenon is attributed to the physicochemical characteristics of CLX. As described before, in SLS dissolution medium, amorphous CLX exhibited a lower dissolution rate compared
5. Conclusion The presence of PVP-K30 and ISO in solid dispersion systems of celecoxib was able to change the physicochemical characteristics of CLX. These physicochemical changes increased the dissolution rate and saturation solubility of CLX, although the enhancement was more pronounced when PVP was used. Spray drying generated uniform micronized particles with a higher dissolution rate compared to those of the untreated physical mixtures. In addition, fast solvent evaporation through spray drying produces an amorphous state that usually exhibits an improved dissolution rate. Because of the different dissolution behaviors of amorphous/crystalline CLX in the two dissolution media certified by the US FDA, in vitro analysis for CLX should be done precisely. Further studies should investigate which of these two media best simulates the in vivo conditions, and whether the in vitro results are consistent with the in vivo results. Conflicts of interest The authors declare that there is no conflict of interest regarding to 195
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this manuscript.
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Acknowledgement Financial support from the vice chancellor for research of Isfahan University of Medical Sciences, Iran (Grant no.394233) is greatly appreciated. References [1] Y. Shono, E. Jantratid, N. Janssen, F. Kesisoglou, Y. Mao, M. Vertzoni, C. Reppas, J.B. Dressman, Prediction of food effects on the absorption of celecoxib based on biorelevant dissolution testing coupled with physiologically based pharmacokinetic modeling, Eur. J. Pharm. Biopharm. 73 (2009) 107–114. [2] M. Lindenberg, S. Kopp, J.B. Dressman, Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system, Eur. J. Pharm. Biopharm. 58 (2004) 265–278. [3] G. Chawla, P. Gupta, R. Thilagavathi, A.K. Chakraborti, A.K. Bansal, Characterization of solid-state forms of celecoxib, Eur. J. pharm. sci. official J. Eur. Fed. Pharm. Sci. 20 (2003) 305–317. [4] T.f. Vasconcelos, B. Sarmento, P. Costa, Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs, Drug Discov. Today 12 (2007) 1068–1075. [5] C. Leuner, J. Dressman, Improving drug solubility for oral delivery using solid dispersions, Eur. J. Pharm. Biopharm. 50 (2000) 47–60. [6] H. Chen, C. Khemtong, X. Yang, X. Chang, J. Gao, Nanonization strategies for poorly water-soluble drugs, Drug Discov. Today 16 (2011) 354–360. [7] E. Merisko-Liversidge, G.G. Liversidge, E.R. Cooper, Nanosizing: a formulation approach for poorly-water-soluble compounds, Eur. J. Pharmaceut. Sci. 18 (2003) 113–120. [8] N. Blagden, M. de Matas, P.T. Gavan, P. York, Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates, Adv. Drug Deliv. Rev. 59 (2007) 617–630. [9] R. Challa, A. Ahuja, J. Ali, R.K. Khar, Cyclodextrins in drug delivery: an updated review, AAPS PharmSciTech 6 (2005) E329–E357. [10] A. Paudel, Z.A. Worku, J. Meeus, S. Guns, G. Van den Mooter, Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: formulation and process considerations, Int. J. Pharm. 453 (2013) 253–284. [11] P. Gupta, R. Thilagavathi, A.K. Chakraborti, A.K. Bansal, Role of molecular interaction in stability of celecoxib-PVP amorphous systems, Mol. Pharm. 2 (2005) 384–391. [12] P. Gupta, V.K. Kakumanu, A.K. Bansal, Stability and solubility of celecoxib-PVP amorphous dispersions: a molecular perspective, Pharmaceut. Res. 21 (2004) 1762–1769. [13] G.P. Andrews, O. Abu-Diak, F. Kusmanto, P. Hornsby, Z. Hui, D.S. Jones, Physicochemical characterization and drug-release properties of celecoxib hot-melt
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Preparation and characterization of solid dispersions of celecoxib obtained by spray-drying ethanolic suspensions containing PVP-K30 or isomalt
T
Saeed Motallae, Azade Taheri, Alireza Homayouni∗ Department of Pharmaceutics, School of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
A R T I C LE I N FO
A B S T R A C T
Keywords: Celecoxib Isomalt PVP Solid dispersion Spray drying
Celecoxib (CLX) is an anti-inflammatory drug that is used for acute pain treatment, but it has very low oral bioavailability owing to its poor water solubility. In this study, CLX solid dispersions are prepared by spraydrying using hydrophilic carriers with the aim of improving its apparent solubility and dissolution rate. Blends with different ratios of CLX, isomalt (ISO) and PVP were prepared in ethanol, and solid dispersions were obtained using a spray dryer. The saturation solubility and dissolution kinetics in 0.25% SLS and 0.04 M Na3PO4 containing media were determined. Also, SEM, DSC, XRPD, and stability studies were used to characterize the systems. Physicochemical analysis demonstrated the presence of amorphous CLX in the spray dried samples. The saturation solubility and dissolution rate of CLX from these formulations were higher than those for pure celecoxib and its physical mixtures. Amorphous CLX showed a lower dissolution rate compared to its crystalline form in 0.25% SLS medium, while this tendency was reversed under alkaline conditions. The CLX:PVP:ISO 3:5:2 spray dried sample showed the highest dissolution rate in both media. Exposure of samples to high moisture (75% humidity) recrystallized some of the amorphous CLX. Thus, the results showed that the dissolution rate of CLX was enhanced in 0.25% SLS, whereas a reduction in dissolution rate was observed in 0.04 M Na3PO4.
1. Introduction Celecoxib (CLX) is a nonsteroidal anti-inflammatory drug (NSAID) that is used for the treatment of acute pain, such as osteoarthritis, rheumatoid arthritis, and dysmenorrhea. However, its poor water solubility (1–3 μg/ml) restricts its oral bioavailability to about 30% [1]. According to the biopharmaceutical classification system (BCS), CLX can be categorized as a Class II drug (poorly water soluble and high gastrointestinal permeability). In this class, dissolution is the rate-limiting step for absorption from the gastrointestinal tract; thus, with increasing solubility and dissolution rate, the oral bioavailability of these drugs improves [2]. Moreover, celecoxib, with needle-like crystalline shape, suffers from poor pharmaceutical properties, particularly unfavorable compressibility and poor flowability [3]. These conditions create various problems with the preparation of a solid dosage form in the pharmaceutical industry. Thus, it is important to improve the physicochemical and physicomechanical properties of celecoxib to enhance its solubility and flowability. Various strategies have been used to improve the poor water solubility of hydrophobic drugs. For example, making solid dispersions [4,5], reducing the particle size [6,7], cocrystallization [8], and the cyclodextrins [9] have been used before in recent years to improve the
∗
solubility and dissolution behavior of these drugs. Among these techniques, preparation of solid dispersion formulations of the active pharmaceutical ingredient (API) is one of the most favorable strategies owing to its simple and cost-effective method of preparation. In these systems, the API is simply dispersed in a non-pharmacological and safe carrier. The carrier must have good hydrophilic properties so that it can dissolve in water and hydrate the hydrophobic API [5]. Typically, polymers are used as carriers so the solid-state matrix and the API are usually amorphous. In these conditions, the drug in amorphous form exhibits a higher dissolution rate owing to its weaker lattice structure compared to in its crystalline state [4]. Moreover, in solid dispersion systems, a reduction in the drug's particle size (sometimes to the molecular level) can lead to enhancement of the dissolution rate and oral bioavailability of poorly water-soluble drugs. Melting and solvent evaporation are the most common methods used for the preparation of solid dispersion formulations. In the solvent evaporation technique, the API and carrier are simply dissolved in a common solvent, and then the solvent is evaporated to obtain a solid dispersion of the drug and carrier [5]. Spray drying is an effective technology for the preparation of solid dispersions. In this method, fast solvent evaporation leads to rapid transformation of the API–carrier solution to a solid API–carrier matrix [10].
Corresponding author. E-mail addresses: [email protected], [email protected] (A. Homayouni).
https://doi.org/10.1016/j.jddst.2018.05.020 Received 31 January 2018; Received in revised form 13 May 2018; Accepted 13 May 2018 Available online 15 May 2018 1773-2247/ © 2018 Elsevier B.V. All rights reserved.
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Table 1 Spray-drying yield and theoretical vs. actual percent drug loading of solid dispersions. Solid dispersions
Yield of spray dryer(%)
Theoretical drug loading(%)
Actual drug loading(%)
Saturation solubility (μg/ml)
Raw CLX CLX SD CLX:ISO 7:3 SD CLX:ISO 5:5 SD CLX:ISO 3:7 SD CLX:ISO 1:9 SD CLX:PVP:ISO 3:5:2 CLX:PVP:ISO 3:2:5 CLX:ISO 7:3 PM CLX:ISO 5:5 PM CLX:ISO 3:7 PM CLX:ISO 1:9 PM CLX:PVP:ISO 3:5:2 CLX:PVP:ISO 3:2:5
_ _ 30.1 49.2 50.3 53.7 52.6 51.5 _ _ _ _ _ _
_ _ 70 50 30 10 30 30 _ _ _ _ _ _
_ _ 66.9 ± 0.4 41.5 ± 0.5 24.1 ± 0.5 5.8 ± 0.3 19.7 ± 0.3 25.8 ± 0.1 _ _ _ _ _ _
0.96 1.10 1.97 3.11 2.75 3.28 5.41 3.87 1.92 1.66 1.86 1.78 2.69 2.14
SD SD
PM PM
± ± ± ± ± ±
1.5 1.2 2.5 1.5 2.5 2.1
± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.02 0.05 0.07 0.13 0.04 0.14 0.20 0.11 0.06 0.07 0.10 0.02 0.08 0.14
spray drying was performed with the following conditions: inlet temperature 105 °C, outlet temperature 60 °C, suspension flow rate of about 5 mL/min, and N2 atomized flow rate of 35 m3/h. The spray-dried particles were stored in closed vials until needed for further studies.
Several formulation approaches have been used before to improve the solubility and dissolution behavior of CLX. Preparation of CLX solid dispersions in PVP, HPMC, PVA, PEG, poloxamer 188, Soluplus®, and Kollicoat® has been reported before [11–17]. PVP K30 has been used to produce homogenous, stable, amorphous solid dispersions of CLX and reduce the particle size to the molecular level, thus making this polymer a promising carrier for solid dispersion formulations of CLX [11,13,18]. Beside the good performance of PVP as a hydrophilic carrier for enhancing the dissolution of CLX, sugar alcohols such as isomalt (ISO) could provide appropriate physicochemical properties for solid dosage forms. ISO, which has half the sweetening potency of sugar but similar taste, is used as a sweetener in the food and pharmaceutical industries. This sugar does not decompose in the mouth and does not decay teeth, so it is a good alternative to sucrose for use in the food and pharmaceutical industries. In addition, ISO can be used as a filler and binder in tablets, especially in oral disintegration tablets (ODTs), owing to its good mechanical properties [19–21]. Moreover, the large number of hydroxyl groups in its structure and high water solubility of this sugar make ISO a suitable carrier for solid dispersion formulations [22]. In this study, the effects of different ratios of PVP K30 and isomalt (Galen IQ 810) in CLX solid dispersions obtained from alcoholic suspensions were investigated. In addition, the effects of moisture on the physicochemical properties of the solid dispersions after 1 month of storage were demonstrated.
2.2.2. Preparation of physical mixtures of drug/Carrier (PM) The physical mixtures of CLX, ISO, and PVP-K30 with the same ratios as those used in the spray drying method were prepared by mixing the sieved fractions (smaller than 250 μm) of compounds using mortar and pestle. 2.2.3. Determination of spray-drying yield and drug loading The yields of the spray-dried samples were calculated by dividing the weight of the recovered particles by the total solid content of CLX and carrier(s) used in the ethanolic suspension. For determination of the drug loading, an accurately weighed amount of each solid dispersion formulation was dissolved an appropriate amount of hydroethanolic solution (70% ethanol in this case) and the concentration of CLX was determined spectrophotometrically based on a calibration curve obtained for CLX at 253 nm wavelength. Preliminary studies showed that the UV absorption of PVP and ISO did not show any interference with CLX at 253 nm. 2.2.4. Scanning electron microscope (SEM) The morphologies of pure CLX, pure ISO, and the spray-dried samples were examined at magnifications of 1000 × and 2000 × using a scanning electron microscope (Philips X series, Netherlands) at an acceleration voltage of 20 kV. Samples were coated with a thin gold–palladium layer by sputter coater (SC 7620, England).
2. Materials and methods 2.1. Materials Celecoxib was purchased from Arastoo Pharmaceutical chemical Inc. (Iran). PVP-K30 was purchased from Sigma-Aldrich (Germany), sodium lauryl sulfate (SLS) was obtained from Merck (Germany), and isomalt (Galen IQ 810) was kindly donated by Beneo Palatinit (Germany). All other solvents and chemicals were of analytical grade.
2.2.5. Determination of saturation solubility Saturated solubility tests were performed on pure CLX as well as the solid dispersion formulations and their physical mixtures. An excess amount of each sample (equivalent to 2 mg of CLX) was added to 10 mL of double-distilled water in a 25 mL, beaker which was sealed with Parafilm® and was shaken at 200 rpm in an air bath (25 °C) for 48 h. After 48 h, the resulting suspensions were filtered through a 0.22-μm cellulose acetate filter (Biofil MCE membrane). The concentration of CLX was determined spectrophotometrically at 253 nm (UV spectrophotometer, Shimadzu, Japan). The solubility of each sample was determined in triplicate and the results reported as means and standard deviations.
2.2. Methods 2.2.1. Preparation of CLX:ISO:PVP solid dispersions via spray drying (SD) Accurate amounts of different ratios of CLX and ISO (7:3, 5:5, 3:7, 1:9) and CLX, ISO and PVP (3:5:2, 3:2:5) were weighed. The aforementioned ratios of celecoxib and isomalt were dispersed in a specific amount of 96% ethanol since celecoxib is soluble in ethanol. However, isomalt is insoluble in ethanol, so a specific type of isomalt (Galen IQ 810) with a small particle size (mean particle size: 22 μm) was used in order to prevent blocking of the spray dryer nozzle. The spray drying operation was performed using a B290 mini spray dryer with a B-295 inert loop (Büchi Labortechnik AG, Flawil, Switzerland). Appropriate mass ratios were prepared from 2% w/v ethanolic suspensions. The
2.2.6. Differential scanning calorimetry (DSC) Differential scanning calorimetry (DSC) studies were performed using a DSC 822e (Mettler Toledo, Switzerland) equipped with a refrigerator cooling system. Samples of the physical mixtures and spraydried formulations (2–3 mg) were placed in aluminum pans sealed with 189
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Fig. 1. SEM image of (A) pure celecoxib, (B) isomalt, (C) CLX:ISO 7:3 SD, (D) CLX:ISO 5:5 SD, (E) CLX:ISO 3:7 SD, (F) CLX:ISO 1:9 SD, (G) CLX:PVP:ISO 3:2:5 SD, (H) CLX:PVP:ISO 3:5:2 SD.
2.2.8. Dissolution studies In order to monitor the dissolution profiles of the prepared CLX formulations, two different dissolution media were used with the USP Apparatus 2 dissolution test (paddle method).
a lid. The crimped aluminum pans were placed inside the DSC and were scanned from 20 to 200 °C at a scanning rate of 10 °C/min under nitrogen gas at a flow rate of 80 mL/min. Melting points and endothermic enthalpies were calculated using the software provided with the instrument (STARe Ver. 12.00 Mettler Toledo, Switzerland).
i For the first dissolution medium, each vessel was filled with 1000 mL of distilled water containing 0.25% w/v Sodium lauryl sulfate (SLS) equilibrated to 37 °C and the paddles were rotated at 50 rpm (as used in our previous studies) [18,23,24]. ii In order to maintain the sink conditions during the dissolution process, the US FDA has approved alkaline medium for the
2.2.7. X-ray powder diffraction studies (XRPD) X-ray powder diffraction (XRPD) measurements were carried out on selected samples using a D8 Advance diffractometer (Bruker, Germany) with Cu Kα radiation (λ = 1.54 Å). Each sample was scanned in the range of 5–80° (2Ɵ) with a step size of 0.05. 190
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dissolution profile of the spray-dried samples, they were stored at 75% humidity (prepared with saturated NaCl solution) and 25 °C for 1 month. After the storage, dissolution tests and XRPD analyses were performed. The dissolution profiles were compared by calculating the similarity factor (f2) using the following equation:
⎧⎡ 1 f2 = 50 log ⎢1 + ⎨ n ⎩⎣
n
−0.5
∑ (Rt − Tt )2⎤⎥ t=1
⎦
⎫ × 100 ⎬ ⎭
(3)
Where n is the sampling number and Rt and Tt are the percentage of dissolved at time point t from the reference and test samples, respectively. If the f2 value is between 50 and 100, the dissolution profiles of the two samples are considered to be equivalent [25]. 3. Results 3.1. Determination of spray-drying yield and drug loading
Fig. 2. DSC trace of raw CLX and spray dried (SD) sample.
The spray-drying yield and drug loading are presented in Table 1. The percentage yield varied between 30% and 53% depending on the ratios of the carriers. An increase in the carrier ratio resulted in an increased yield of celecoxib in the drug product. As shown in Table 1, the actual drug loading is always lower than the theoretical drug loading; however, as the celecoxib ratio decreases, the difference between the actual drug loading and theoretical loading increases.
Table 2 Melting points and enthalpies of fusion for samples prepared by spray drying. N/D = not defined. Peak 1
CLX CLX:ISO 7:3 CLX:ISO 5:5 CLX:ISO 3:7 CLX:ISO 1:9 CLX:ISO:PVP 3:5:2 CLX:ISO:PVP 3:2:5
Peak 2
Peak 3
°C
ΔH (J/g)
°C
ΔH (J/g)
°C
ΔH (J/g)
– 98.56 98.64 97.69 101.88 98.72 –
– 0.82 1.05 3.29 6.62 0.89 –
– 151.93 152.07 152.57 154.56 151.94 –
– 5.05 7.85 33.68 38.25 4.65 –
162.24 162.05 161.94 161.68 160.79 – –
99.83 56.72 33.30 16.31 N/D – –
3.2. Scanning electron microscope (SEM) results SEM was used to investigate the effect of the spray-drying process on the morphology of the obtained samples. SEM images of pure CLX, ISO, and the spray-dried samples are shown in Fig. 1. Pure celecoxib crystals exhibited rod-shape morphology (Fig. 1A) while the ISO particles have an irregular shape and a particle size of approximately 20 μm (Fig. 1B). In the spray-dried samples containing ISO (Fig. 1C, D, E and F), the celecoxib particles presented as needle-shaped crystals on the surface of the ISO particles while in the samples containing PVP, the obtained particles were spherical with almost smooth surfaces (Fig. 1G and H). On increasing the PVP ratio in these samples, this property becomes more pronounced.
dissolution of celecoxib capsules. Therefore, for the second dissolution medium, each vessel was filled with 1000 mL of tribasic sodium phosphate (0.04 M; pH = 12) equilibrated to 37 °C and the paddles were rotated at 50 rpm [24]. An accurate weight of the samples equivalent to 40 mg of CLX powder was placed at the top of the dissolution medium. 5-mL Samples were withdrawn from the vessels, replaced with fresh dissolution medium, and immediately filtered through 0.22-μm cellulose acetate filters (Biofil MCE membrane). The concentration of CLX was determined spectrophotometrically at 253 nm (Shimadzu, Japan) based on a calibration curve obtained for CLX at this wavelength. The dissolution of each sample was carried out in triplicate. PVP and ISO showed no absorption at 253 nm. The dissolution efficiency (DE) and mean dissolution time (MDT) were calculated to reflect the dissolution performance of the prepared CLX formulations. DE is defined as the area under the dissolution curve (y) up to a certain time t, expressed as a percentage of the area of the rectangle described by 100% dissolution in the same time [25]. It is calculated as follows:
DE% =
t ∫0 y.dt
y100.t
× 10
3.3. Determination of saturation solubility The saturation solubility levels for pure CLX, the physical mixtures, and the solid dispersions are reported in Table 1. The saturation solubility of all the prepared samples was significantly increased in comparison to that of pure CLX (P value < 0.05). There was no significant difference between the solubility of the untreated CLX and the spraydried CLX (P > 0.05). The saturation solubility of the CLX:PVP:ISO 3:5:2 SD sample is 5.4 μg/mL, which is about six times greater than the solubility of the pure drug. 3.4. Results of DSC study The DSC thermograms of pure CLX and selected samples are shown in Fig. 2. Pure CLX exhibited a sharp endothermic peak at around 162 °C, which was attributed to its melting point and is in agreement with previously published data [3]. As shown in Fig. 2, all the obtained samples have a small endothermic peak at around 90–100 °C while the enthalpy of the first peaks increases with increasing ISO ratio. In addition to the first peak, the CLX:ISO samples exhibited two peaks close to each other at around 150 °C (2nd peak) and 162 °C (3rd peak). Increasing the ISO ratio in these samples resulted in an enhancement of the enthalpy of fusion for the second peak and a reduction in the enthalpy of fusion for the third peak. In the samples containing PVP, the intensity of the peaks has decreased substantially such that for the CLX:PVP:ISO 3:5:2 sample the peaks have almost completely
(1)
MDT is calculated using the following equations. −
MDT = ∑ ti . ΔMi ∑ ΔMi
− ti = (ti + ti + 1 ) 2
ΔMi = (Mi + 1 − Mi ) (2)
t i is the midpoint of the time period during which the fraction Where − ΔM of the drug is released from the sample. 2.2.9. Stability test In order to investigate the effect of moisture on the solid state and 191
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Fig. 3. XRD pattern of CLX, ISO and selected samples.
3.5. XRPD results
accelerated the dissolution rate of almost all the samples. This enhancement is more pronounced in the SD samples. Moreover, samples containing PVP show higher dissolution rates compared to those of the other samples. According to Table 3, the CLX:PVP:ISO 3:5:2 SD sample exhibited the highest DE60% and the lowest MDT. The key result is the lower DE60% and higher MDT of the CLX SD samples compared to those for raw CLX.
Fig. 3 shows the XRPD patterns for selected samples. Pure CLX exhibited sharp characteristic peaks at 5, 10.5, 15, and 21.53 angle, which indicate the crystalline nature of CLX [3]. PVP-K30 does not exhibit any obvious peaks owing to its amorphous nature, but ISO shows different distinct peaks related to its crystalline structure [24]. The physical mixture samples (CLX:ISO 1:9 PM and CLX:ISO:PVP 3:5:2 PM) have sharp peaks relating to CLX and ISO that are still visible, although their intensity has decreased slightly. However, in the samples prepared by spray drying, the intensity of these peaks has substantially decreased. This result is more pronounced in samples containing PVP.
3.6.2. Dissolution studies in Na3PO4 (0.04 M, pH 12) This medium has been defined by US FDA previously due to maintenance sink condition. As shown in Fig. 4C and D, similar results were obtained for the SD and PM samples. Similar to the first medium, samples containing higher amounts of carrier showed higher dissolution rates. However, this enhancement is more pronounced owing to the sink conditions in Na3PO4 medium. Interestingly, in this medium spray-dried CLX without any additive (CLX SD) presented a higher dissolution rate than that obtained for pure CLX.
3.6. Dissolution study results
3.7. Stability test results
In order to investigate the dissolution profiles of the CLX formulations, two different dissolution media were used.
Recrystallization of the amorphous drug is the biggest problem with solid dispersion formulations. The amorphous drug in these formulation has a greater tendency to recrystallize in the presence of humidity during storage [4]. In this study, XRPD patterns and dissolution behavior of SD samples were investigated after 1 month of storage at a
disappeared. Table 2 shows the changes in the enthalpy of fusion related to various samples prepared by spray drying. In these samples, with increasing ISO ratio the enthalpy of peak 3 (related to CLX) decreases while the enthalpy of peak 2 (related to ISO) increases.
3.6.1. Dissolution studies in 0.25% SLS As shown in Fig. 4, it is clear that the presence of ISO and PVP-K30 192
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Fig. 4. Dissolution profile of pure CLX and Physical mixture (PM) samples in SLS 0.25%(A), pure CLX and spray drying (SD) samples in SLS 0.25% (B) pure CLX and PM samples in Na3PO4 0.04 M(C) pure CLX and SD samples in Na3PO4 0.04 M (D). Table 3 Dissolution efficiency (DE) and mean dissolution time (MDT) in different media of raw CLX and the samples prepared with physical mixtures (PM) or spray-drying (SD) process and also similarity factor (f2) of SD samples after 1 month storage (75% humidity and 25 °C). Sample name
DE% in 0.25% SLS
MDT in 0.25% SLS (min)
DE% in Na3PO4
MDT in Na3PO4 (min)
f2 in 0.25% SLS
f2 in Na3PO4
Raw CLX CLX SD CLX:ISO 7:3 PM CLX:ISO 5:5 PM CLX:ISO 3:7 PM CLX:ISO 1:9 PM CLX: PVP:ISO 3:2:5 CLX: PVP:ISO 3:5:2 CLX:ISO 7:3 SD CLX:ISO 5:5 SD CLX:ISO 3:7 SD CLX:ISO 1:9 SD CLX: PVP:ISO 3:2:5 CLX: PVP:ISO 3:5:2
21.86 13.02 52.01 28.67 31.74 44.02 42.11 48.67 43.75 46.17 51.91 44.02 73.86 77.04
24.25 ± 0.81 26.94 ± 0.43 9.35 ± 0.35 10.49 ± 1.48 7.03 ± 0.32 4.82 ± 0.91 13.59 ± 0.12 13.21 ± 0.92 10.71 ± 0.67 8.53 ± 0.78 16.06 ± 0.29 4.82 ± 0.8 2.9 ± 0.42 1.07 ± 0.23
52.05 59.04 43.32 52.74 54.12 58.04 59.53 63.54 65.41 79.71 75.75 87.03 93.05 94.45
23.32 ± 0.91 21.60 ± 0.58 15.94 ± 0.59 14.9 ± 0.11 14.1 ± 0.58 17.61 ± 0.49 21.22 ± 0.38 19.53 ± 0.42 17.24 ± 0.61 6.13 ± 0.89 13.79 ± 0.53 12.57 ± 0.52 2.93 ± 0.63 3.22 ± 0.19
– – – – – – – – 41.82 44.51 42.53 41.83 53.90 56.74
– – – – – – – – 32.97 37.84 33.56 41.63 72.11 58.54
PM PM
SD SD
± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.91 0.52 0.62 0.47 0.31 0.63 0.25 0.61 0.55 0.43 0.33 0.63 0.93 0.35
± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.55 0.91 0.36 0.61 0.12 0.87 0.71 0.88 0.65 0.83 0.26 0.61 0.53 0.43
significantly, but the dissolution rate for the samples without PVP decreased. For example, more than 60% of the drug was released after 10 min in the freshly prepared sample of CLX:ISO 7:3 SD while after 1 month of storage the amount of drug released after 10 min had reduced to 40%.
humidity of 75% and a temperature of 25 °C. The XRPD patterns and dissolution profiles of selected samples before and after storage are shown in Figs. 5 and 6. As shown in Fig. 5, the characteristic peaks of CLX are not present in the freshly prepared SD samples. However, after storage a slight increase in the intensity of the characteristic CLX peaks could be observed in for the CLX:ISO 1:1 SD and CLX:ISO 1:9 SD samples. This increase was not observed for the samples containing PVP. The results from the dissolution tests after 1 month of storage are presented in Fig. 6. As shown in Fig. 6A, after storage the dissolution rate increased slightly for samples containing ISO without PVP. For example, in the freshly prepared CLX:ISO 1:9 SD sample, about 30% of the drug was released after 5 min while after 1 month of storage, about 45% of the drug was released in the same timeframe. However, in all the samples containing PVP, the dissolution rate did not change significantly. The results for the dissolution tests carried out in 0.04M Na3PO4 after 1 month of storage are shown in Fig. 6B. As shown in the figure, the dissolution rate in samples containing PVP did not change
4. Discussion As shown in Table 1, the percentage yield varied between 30% and 53% depending on the ratio of the carriers. On increasing the carrier ratio (PVP or ISO), the yield increased. This phenomenon is attributed to the presence of ISO. In samples with a high ratio of ISO, the solid content in the suspension is increased. Ethanol 96% was used for spray drying, but ISO does not dissolve completely in ethanol so the micronized particles of ISO became trapped in the collector of the spray dryer while the CLX molecule (which dissolves in ethanol) must be arrangement from its molecular size and forms fine particles. Obviously, during this bottom-up process, the fine particles of CLX are generated alongside the micronized particles, which could escape from the collector 193
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samples, especially in the formulations containing PVP, CLX and PVP generated matrices containing molecular dispersions of CLX and PVP in their structures, which does not occur in the PM samples. The XRPD and DSC results have clearly shown the amorphous state of CLX in these matrices. As mentioned before, in addition to its melting point, pure ISO shows a small broad endothermic peak at around 100 °C, which is attributed to the evaporation of water during heating. The grade of ISO (Galen IQ 810) used in this work contains about 3% water according to the manufacturer (Beneo Palatinit, Germany). As shown in Fig. 2, as the ISO ratio increases, this peak becomes more pronounced. The second peak at around 150 °C is attributed to the melting point of ISO and the third peak is attributed to the melting point of CLX. Since the ratios of ISO are different in the different SD samples, this difference is presented as an enthalpy of fusion in Table 2. Moreover, in the CLX:ISO 1:9 SD sample these two peaks overlapped, which could be caused by the interaction of CLX and ISO during heating or the dissolution of a small amount of ISO in ethanol and its subsequent dispersion with CLX molecules during the spray-drying process. In samples containing PVP, the intensity of all the peaks was decreased, with the CLX:PVP:ISO 3:5:2 SD sample showing no peaks. These results indicated the presence of CLX and ISO in an amorphous state. It has been shown before that CLX and PVP can generate amorphous solid dispersions after spray drying from ethanolic solution [18]. Similar results were obtained from the XRPD studies. As mentioned in the results section, SD samples exhibited lower peak intensities compared to the respective PM samples. For example, in the samples containing PVP (specifically in CLX:PVP:ISO 3:5:2 SD), almost all the characteristic peaks of CLX were diminished. The halo pattern from the XRPD analysis exhibited that the majority of this sample exists in the amorphous state. The amorphous nature of the SD samples could be attributed to the amorphous nature of PVP itself and the fast crystallization of CLX during spray drying. These results are in good agreement with those from DSC studies. Generally, PVP-K30 and ISO (owing to their hydrophilic characteristics) increased the saturation solubility and dissolution rate of CLX in the solid dispersion samples (Fig. 4). As PVP is a hydrophilic polymer, it surrounds the surface of hydrophobic drugs, which, in turn, makes the surface of hydrophobic drug particles more hydrophilic, hence enhancing the wettability of the drug particles for improved dissolution. Moreover, in the SD samples containing PVP, the CLX molecules were present in the amorphous state and amorphous solid dispersion matrices were produced. It has been proved in several previous studies that amorphous solid dispersion systems exhibit higher saturation solubility compared to those for pure drugs or their physical mixtures. These results are more pronounced when the drug participates in hydrogen bonding with the carrier(s) [4,5,18]. As shown in Fig. 4, the lower dissolution rate of CLX SD compared to pure CLX (crystalline form) in 0.25% SLS is noteworthy. This result is converse to that obtained in alkaline medium (0.04 M Na3PO4). Similar results have been reported before by Ghanavati et al. [24]. This phenomenon could be attributed to the devitrification of amorphous CLX in the dissolution medium, as described before for other drugs [27–29]. However, under alkaline conditions, the spray-dried CLX exhibited a higher dissolution rate. As we described in a previous study, amorphous CLX could participate in intermolecular hydrogen bonding, but this hydrogen bonding could break down under alkaline conditions (by power of OH); however, this event does not happen when these samples are introduced to 0.25% SLS dissolution medium. As mentioned before, in samples containing high levels of carrier, such as CLX:PVP:ISO 3:5:2 SD, the dissolution rate is higher than all of other samples (Fig. 4B and D). Although CLX is present in the amorphous state in these samples, in this case, CLX participates in hydrogen bonding with PVP and forms a uniform solid dispersion matrix. This state accelerates the hydration of CLX molecules owing to the hydrophilicity of PVP and ISO, hence the observed enhancement of the dissolution rate. Moreover, in these
Fig. 5. XRPD pattern of some prepared samples using spray dryer before and after 1-month storage in 75% humidity and 25 °C temperature.
and become trapped in the outlet filter. Therefore, the yield from spray drying is higher when the ratio of ISO is higher than that of CLX. This justification also explains the lower amount of actual drug loading obtained versus the theoretical drug loading, as presented in Table 1. Regarding Table 1, the actual drug loading of CLX in the CLX:ISO 1:9 SD sample is about 50% of its theoretical drug loading, while in samples with higher ratios of CLX this difference is not seen. The percentage yield and actual drug loading in the samples containing PVP are favorable. The presence of PVP increased the viscosity of the suspension so the production of particles that can settle in the collector, and hence the yield from the spray dryer, have increased. The desirable properties of PVP for the spray-drying process have been demonstrated before in numerous studies [10,18]. As shown in Fig. 1, for the spray-dried samples containing ISO (Fig. 1C, D, E, and F), celecoxib particles (with needle-like crystalline shape) covered the ISO particles. This morphology could be attributed to the fast evaporation of ethanol during spray drying. In this case, before spray drying the suspended ISO particles are surrounded with dissolved CLX in ethanol, so after rapid evaporation of the ethanol, CLX molecules cover the ISO particles. However, after a while, CLX molecules recrystallized to crystalline form and exhibited a needle-like crystal form. In the samples containing both PVP and ISO, the presence of PVP resulted in spherical and uniform particles. It seems that PVP K30 is able to create spherical particles because of its solubility in ethanol and inhibiting the crystal growth of CLX during crystallization (solvent evaporation in the spray-drying process). The effect of PVP as a crystal growth inhibitor has been proved for CLX [11,12] and other drugs before [10,26]. Table 1 shows that the SD samples exhibited higher saturation solubility compared to that of pure CLX (P < 0.05). In addition, all of the SD samples exhibited significant solubility enhancement compared to the respective PM samples (P < 0.05), except for CLX:ISO 7:3. These results could be owing to the different physicochemical characteristics of these samples. In the SD samples, CLX is dissolved in ethanol and is converted to an amorphous state after spray drying. Moreover, in these
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Fig. 6. Dissolution profile of spray dried samples in SLS 0.25% medium (A) and in Na3PO4 0.04 M medium (B) after 1-month storage in 75% humidity and 25 °C temperature.
to its crystalline form; therefore, the conversion of a portion of the amorphous CLX to its crystalline state (during storage in humid conditions) caused a higher dissolution rate compared to the freshly prepared amorphous CLX. The reverse was seen in Na3PO4 medium.
samples, CLX has been dispersed molecularly in the PVP/ISO matrix. In 0.25% SLS, the dissolution enhancement for samples containing more than 50% carrier is obvious. For example, in the CLX:PVP:ISO 3:5:2 SD sample, after 5 min almost 90% of the drug was released while the release of pure CLX did not even reach 40% after 60 min (Fig. 4B). Generally, it is obvious that the CLX dissolution has been enhanced in almost all of the SD samples (Fig. 4), although in Na3PO4 medium the dissolution rate was affected more significantly. This result is attributed to the better dissolution of CLX in alkaline media because of the sink conditions. According to XRPD results (Fig. 5), it is clear that the samples without PVP have recrystallized after 1 month of storage at 75% humidity (CLX:ISO 1:1 and 1:9). However, the amorphous state of CLX was retained in the solid dispersion samples containing PVP. It seems that PVP was able to protect the drug from recrystallization in these samples (Fig. 5). It has been demonstrated before that in solid dispersion formulations the use of a carrier with a high glass transition temperature (Tg) can increase the Tg of the solid dispersion system and protect the amorphous state of the drug from recrystallization [30]. Analysis of dissolution behavior in 0.25% SLS medium showed an increase in the dissolution rate of CLX after 1 month of storage, while the dissolution rate of CLX was decreased in Na3PO4 medium after 1 month of storage (Fig. 6). This phenomenon is attributed to the physicochemical characteristics of CLX. As described before, in SLS dissolution medium, amorphous CLX exhibited a lower dissolution rate compared
5. Conclusion The presence of PVP-K30 and ISO in solid dispersion systems of celecoxib was able to change the physicochemical characteristics of CLX. These physicochemical changes increased the dissolution rate and saturation solubility of CLX, although the enhancement was more pronounced when PVP was used. Spray drying generated uniform micronized particles with a higher dissolution rate compared to those of the untreated physical mixtures. In addition, fast solvent evaporation through spray drying produces an amorphous state that usually exhibits an improved dissolution rate. Because of the different dissolution behaviors of amorphous/crystalline CLX in the two dissolution media certified by the US FDA, in vitro analysis for CLX should be done precisely. Further studies should investigate which of these two media best simulates the in vivo conditions, and whether the in vitro results are consistent with the in vivo results. Conflicts of interest The authors declare that there is no conflict of interest regarding to 195
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this manuscript.
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