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Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights
J. DRUG DEL. SCI. TECH., 16 (3) 203-209 2006
Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights J. Shokri1, J. Hanaee2, M. Barzegar-Jalali3, R. Changizi2, M. Rahbar2, A. Nokhodchi3, 4* Research Center of Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran 2 School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran 3 Drug Applied Research Center (DARC), Tabriz University of Medical Sciences, Tabriz, Iran 4 Medway School of Pharmacy, The University of Kent and Greenwich, Central Avenue, Chatham Maritime, Kent, ME4 4TB, United Kingdom *Correspondence: [email protected] or [email protected]
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Indomethacin is an anti-inflammatory drug which is used to relieve pain and inflammatory conditions. For poorly soluble drugs and highly permeable drugs such as indomethacin, the rate of oral absorption is often controlled by the dissolution rate in the gastrointestinal tract. Therefore together with the permeability, the solubility and dissolution behaviour of a drug are key determinants of its oral bioavailability. In this study, an attempt was made to enhance the dissolution rate of indomethacin using various molecular weights of polyethylene glycol (PEG 2000, 6000 and 20000) by a cogrinding technique. The cogrinds containing different drug:PEG ratios (1:1, 1:2, 1:5, 1:10) were made and the dissolution rate of the drug from each of the formulations was studied at different pHs (1.2, 4.6 and 6.8). The results showed a significant increase in the dissolution rate of indomethacin at various pHs from cogrinds formulations, obtained by this cogrinding technique, in comparison to that of the pure drug powder, treated pure drug, or physical mixtures at all studied pHs. The dissolution results did not show significant differences between the dissolution rates of indomethacin from cogrinds containing PEG 2000 with various drug:carrier ratios, whereas these differences were considerably significant for the cogrinds samples containing PEG 20000. These results confirm that the dominant mechanism of low molecular weights of PEG s in increasing the indomethacin dissolution rate from cogrinds is the formation of a thin film of the PEG around the poorly soluble drug particles. In the case of high molecular weight PEGs, such as PEG 20000, since the indomethacin:carrier ratios significantly affected the dissolution rate of indomethacin from the cogrinds, therefore, it seems that the increase in dissolution of indomethacin from these cogrinds was mainly caused by an improved solubility of the drug by the presence of these carriers. The particle size analysis showed small changes in the particle size diameter and powder surface area of indomethacin after grinding (16.3% reduction in median particle diameter and 18.8% increase in the total powder surface area). The XRD and FTIR spectra rejected any polymorphic changes or the production of amorphous indomethacin due to the cogrinding process. These spectra showed only slight changes in the crystal orientation after milling. Key words: Cogrinds – Indomethacin – Dissolution rate – Cogrinding – Physical mixtures – Polyethylene glycols.
Indomethacin ([1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid) is an analgesic, antipyretic and non-steroidal anti-inflammatory drug (NSAID) which is used to relieve pain and inflammatory conditions. Indomethacin is practically insoluble in water and, thus, very slowly dissolves in gastrointestinal fluids. The dissolution rate of poorly water-soluble drugs, such as indomethacin, is one of the most important properties that can greatly influence the therapeutic effect of formulations, especially in the case of drugs that are easily absorbed from the gastrointestinal tract (class II drugs). As the absorption of the poorly soluble drugs from the gastrointestinal tract is limited by the dissolution rate, they often show low bioavailability when administered orally. Therefore, it is important to enhance their dissolution rate. Several methods have been used to improve the dissolution rate of poorly water-soluble drugs such as micronization [1], complexation [2-4], ordered mixture [5], solvent deposition [6], solid dispersion [7-9] and roll mixing [10]. Some of these methods have been applied to the production of pharmaceutical preparations. Among these methods, the solid dispersion techniques are the most effective methods for this purpose. Traditionally, solid dispersions are prepared by coprecipitation [11], coevaporation [4], melting [12] or cogrinding [13, 14] methods. Soluble carriers, such as polyvinyl pyrrolidones, [15], polyethylene glycols (PEGs), [8, 16], hydroxypropylmethylcellulose, [14] carboxy vinyl polymers [17, 18] and carnauba wax, [19] have been used in the preparation of solid dispersions. It has been shown that the dissolution rate of poorly water-soluble drugs, such as diazepam [8], oxazepam [20], furosemide [21], nifedipine [14], carbamazepine [16], piroxicam [32], triamteren [23], indomethacin
[9] and griseofulvin, [14] can be increased by using solid dispersion techniques. The solid dispersion of drugs with hydrophobic carriers, such as Eudragit RL and RS, has been used for preparation of sustained release formulations[17, 24]. In the present study, the dissolution rate of indomethacin from cogrinds made from different polyethylene glycols (PEG 2000, 6000 and 20000) at different pHs (1.2, 4.6 and 6.8) was investigated. Cogrinds with various ratios of drug:PEG were made using a cogrinding method and the dissolution rate of indomethacin from each of them was determined in different dissolution media.
I. MATERIALS AND METHODS
Indomethacin powder was provided by Zahravi Pharmaceutical (Tabriz, Iran). PEG 2000, PEG 6000, PEG 20000 and sodium oleate were purchased from Merck Chemical Co. (Darmstadt, Germany).
1. Preparation of samples
Pure indomethacin powder and each of the PEGs were mixed and charged into the chamber of a vibration ball mill (Fritsch, Utzenhofen, Germany) with various drug-PEGs ratios (1:1, 1:2, 1:5 and 1:10). A certain number of steel balls were added in a way that the total volume of powder mixture and balls equaled one-third the volume of the ball mill chamber. The powder mixtures were ground 3 h at a vibration speed 360 rpm. Then, the samples were collected and the dissolution rate of indomethacin from each of the formulations was measured. For preparation of treated pure drug samples, the drug powders were ground alone in the ball mill under the same conditions used to prepare the cogrinds. Physical mixtures of drug:PEGs were prepared by simple 203
J. DRUG DEL. SCI. TECH., 16 (3) 203-209 2006
Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights J. Shokri, J. Hanaee, M. Barzegar-Jalali, R. Changizi, M. Rahbar, A. Nokhodchi
mixing of the drug powder and each of PEGs with the same ratios that have been used for cogrind formulations. The mass of selected samples for the dissolution study was 25 mg for pure drug powder and treated pure drug, and 50, 75, 125 and 275 mg for cogrinds and physical mixtures formulations with 1:1, 1:2, 1:5, 1:10 drug:PEGs ratios, respectively, such that each sample contained 25 mg indomethacin.
6. Particle size analysis
Median particle size, powder surface area and particle size distribution for the pure drug powder and treated pure drug samples were determined by using a centrifugal particle size analyzer (Shimadzu SA-CP3, Tokyo, Japan) at 2200 rpm with step size of 120 rpm/min. The samples were prepared by adding the suitable amount of the drug powder in water containing sodium oleate as suspending agent. The viscosity of the samples was also measured by a Brookfield LVDVII+ viscometer before particle sizing.
2. Dissolution studies
The dissolution of indomethacin from cogrinds, physical mixtures, untreated pure drug powders and treated pure drug were measured at least in triplicate using a USP 24 standard dissolution apparatus II at 100 rpm (Erweka DT 6R, Heusenstamm, Germany). The dissolution medium was 900 ml of different pH values (1.2, 4.6 and 6.8), which was maintained at 37°C. Samples equivalent to 25 mg of indomethacin was added to 900 ml of dissolution media. At suitable time intervals (5, 10, 15, 30, 60, 120, 240, 360, 480 and 600 min), 5-ml samples were withdrawn and replaced with equal volumes of fresh dissolution media. The concentration of indomethacin in these samples was determined by UV-Visible spectrophotometry (Shimadzu mini 1240, Tokyo, Japan) at 266.5 nm.
II. RESULTS AND DISCUSSION 1. XRD and FT-IR studies
Diffraction spectra of physical mixtures and cogrinds of indomethacin-PEG showed that there were no changes in the spectrum of physical mixtures and coground formulations. For example, the XRD of the physical mixtures of PEG 2000 or PEG 20000 with indomethacin and their coground formulations are shown in Figure 1. The figure shows that each of the principal peaks observed with physical mixtures was present in their respective cogrinds, although with different intensities, and that there was no new peak associated with the cogrinds suggesting the existence of an interaction between the drug and the carrier. Furthermore, the x-ray diffraction patterns of the samples also did not show any polymorphic changes in the samples. The pattern of XRD results of the treated (pure drug powder and cogrinds) and untreated (pure drug powder and physical mixtures) samples demonstrated high similarities to the pattern described in previous studies for the γ polymorph of indomethacin [9, 25, 26]. These include peaks located at 10.2, 11.6, 17.0, 19.6, 20.8, 21.8, 24.0, 26.2 and 29.5° for the γ polymorph of indomethacin. The change in the intensity of indomethacin peaks observed in cogrinds samples as compared to their respective physical mixtures could be due to the change of the crystal orientation during the analysis. In other words, the results indicate that the crystalline nature of the drug in the cogrinds is essentially maintained, but the size of the crystals might have been reduced. The positions of the peaks for the physical mixtures and cogrinds for samples involving the different PEGs were the same and superimposable, which again ruled out the possibility of chemical interaction and compound formation between these two components. FT-IR spectra were used to further characterize the possibility of interactions between indomethacin and PEGs in the solid state. From the structures of indomethacin and PEG it can be assumed that possible interaction could occur between the carboxyl group of indomethacin and the hydroxyl group of PEG . In this case any sign of interaction would be reflected by a change in the O-H vibration, depending on
3. Solubility measurements
Solubility measurements were performed in order to determine the effects of pH, as well as the molecular weight and concentration of the PEGs, on the solubility of indomethacin in these media. To accomplish this, an excess amount of the drug powder was added to 50 ml of the dissolution media with or without a PEG present. The concentrations of PEGs used in the solubility measurements were exactly the same concentrations used in the dissolution studies (0.025, 0.05, 0.125 and 0.25 mg/ml for 1:1, 1:2, 1:5 and 1:10 drug-PEGs ratios, respectively). The solubility tests were performed in triplicate. The drug suspensions with or without PEGs was shaken for 24 h (this duration was previously tested to be sufficient to reach equilibrium) at 37 ± 0.5°C (Heidolph, Incubator 1000, Schwabach, Germany). Subsequently, the samples were filtered through Ashless No. 41 Whatman filter paper (Maidstone, UK) and assayed at the wavelength of 266.5 nm after suitable dilution. After determining the solubility of indomethacin at different pHs in the presence of various PEGs, the solubility enhancement ratio (ER) (solubility of indomethacin in solutions containing a definite concentration of PEG/solubility of indomethacin in the same dissolution media without the PEG) was determined for each concentration of the tested PEG.
4. X-ray diffractometry (XRD)
XRD was used to determine the changes in the crystallinity of indomethacin in the samples during the cogrinding process. Powder X-ray diffraction patterns of samples were recorded using a Zeimens T5000 diffractometer (Munich, Germany) with Ni filtered CuKα line as the source of radiation (40 Kv, 30 mA). The angular range 2-40 2θ was scanned with a step size of 0.02° 2θ at the rate of 1°/min. These spectra were prepared for pure drug powder, treated pure drug, physical mixtures and coground drug-PEG samples at 1:1 ratios in 1.5406 Å wavelength, and the 2θ values of the peaks were compared.
5. Fourier transform infrared (FT-IR) spectroscopy
FT-IR spectra were used to investigate polymorphic changes during the grinding process. These spectra were taken by Bomem MB100 FT-IR series (Quebec, Canada) equipment for untreated pure drug powder, treated pure drug, physical mixtures and cogrinds. The cogrinds and physical mixtures with a 1:1 drug-PEG ratio were chosen for the FT-IR studies. Samples were mixed with KBr powder and compressed to 10-mm discs by a hydraulic press at a pressure of 10 tons for 30 s. The scanning range was 450-4000 cm-1 and the resolution was 2 cm-1.
Figure 1 - XRD of (A) physical mixtures of indomethacin-PEG 2000, (B) coground indomethacin-PEG 2000, (C) physical mixture of indomethacin-PEG 20000, (D) coground indomethacin-PEG 20000.
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Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights J. Shokri, J. Hanaee, M. Barzegar-Jalali, R. Changizi, M. Rahbar, A. Nokhodchi
the extent of interaction. The FT-IR spectra did not show any interaction between indomethacin and PEG in the coground samples. The main identifying peaks in the FT-IR spectrum of indomethacin were described previously by Spychala et al. [27] for determining the type of indomethacin polymorphs. All of the FT-IR spectra for tested samples showed the peaks similar to that described for the γ form of indomethacin (γ = 1,692 and 1,716 cm-1) in the previous articles. In conclusion, the results of the FT-IR and XRD analyses showed that indomethacin did not undergo any polymorphic changes during the cogrinding process and essentially maintained the initial crystalline structure during and after grinding in the absence or presence of various PEGs.
J. DRUG DEL. SCI. TECH., 16 (3) 203-209 2006
[28], an increased wettability of the drug particles [28, 29] and an increase in the solubility of the drug [29, 30]. The X-ray diffraction patterns and FT-IR spectra rejected any changes in the indomethacin crystalline structure. The small difference between the dissolution rates of indomethacin from pure drug and from treated pure drug indicates that the cogrinding process could slightly increase the dissolution rate of treated drug even in the absence of PEG (see Figures 2 to 4). The effects of many different factors on the dissolution rate of indomethacin from physical mixtures and cogrinds have been studied and the results are described below.
3. Effect of PEG on the solubility of indomethacin
Table I shows the ER of various molecular weights of PEGs with different concentrations at different pHs. It can be seen in this table that, at the same concentrations of PEG, the samples containing higher molecular weight PEG have higher ER values at different pHs. The ER values also directly correlated with the concentrations of the PEGs. The highest ER value (4.8) was observed for the highest concentration (250 mg/l) of PEG 20000 at pH 6.8. Moreover, the results showed that the pH of dissolution media did not considerably alter the ER values in the presence of PEG . However, the solubility of indomethacin is greatly affected by the pH of the dissolution media in the absence of PEG, equal to 2.1, 13.2 and 27.5 µg/ml at pH 1.2, 4.6 and 6.8, respectively.
2. Dissolution studies
The effects of many different factors on the dissolution rate of indomethacin from physical mixtures and cogrinds have been studied and the results are described below. The results of the dissolution tests at different pHs are shown in Figures 2 to 4. As shown in these figures, each of the coground formulations exhibited a substantially higher dissolution rate than the pure drug powder or the physical mixtures with the same drug-polymer ratio at the same pH. Several mechanisms have been postulated for an increase in the dissolution rate of drugs from cogrinds containing hydrophilic polymers, such as the PEGs. Some of the suggested mechanisms include micronization
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Figure 2 - Dissolution profiles of indomethacin at pH 6.8 for: (X) pure drug powder; (+) treated pure drug; physical mixtures with ratios of (●) 1:1, (◆)1:2, (■)1:5, (▲)1:10 and solid dispersions with (O)1:1, (◊)1:2, (❐)1:5, (Δ) 1:10 drug:polymer prepared with (A)PEG 2000, (B) PEG6000 and (C) PEG20000.
Figure 3 - Dissolution profiles of indomethacin from different formulations: (X) pure drug powder; (+) treated pure drug; physical mixtures with ratios of (●) 1:1, (◆)1:2, (■)1:5, (▲)1:10 and solid dispersions with (O)1:1, (◊)1:2, (❐)1:5, (Δ) 1:10 drug:polymer prepared with (A)PEG 2000, (B) PEG6000 and (C) PEG20000 at pH 4.6.
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J. DRUG DEL. SCI. TECH., 16 (3) 203-209 2006
Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights J. Shokri, J. Hanaee, M. Barzegar-Jalali, R. Changizi, M. Rahbar, A. Nokhodchi
rate of indomethacin. For instance, the percentage indomethacin dissolved after 5 min from the cogrind samples with the ratios of drug:PEG 20000 1:1, 1:2, 1:5 and 1:10 were approximately 55, 72, 82 and 93% at pH 6.8 (Figure 2C). Similar results can be ruled out for the cogrind samples containing PEG 2000 and 6000 at pH 1.2 or 4.6 (Figures 3 and 4). The correlation between a hydrophilic carrier concentration and the dissolution rate of various drugs from solid dispersions has been observed in other investigations [23, 28, 31]. The drug/carrier ratio in a solid dispersion is one of the main factors affecting the performance of a solid dispersion. It has been shown that if the percentage of the drug were too high (high ratio of drug/carrier), it would form small crystals within the dispersion rather than remaining molecularly dispersed. On the other hand, if the percentage of the carrier were very high (low ratio of drug/carrier), this could lead to the complete absence of crystallinity of the drug and thereby enormous increases in the solubility (see Table I) and dissolution rate of the drug. This could be the reason for the observed increase in the solubility (see Table I) of indomethacin and consequently, the dissolution rate of indomethacin with the increase in the concentration of PEG. An increase in the amount of PEG can also enhance the hydrophilicity of the surface of the solid dispersion particles and this, in turn, reduces the agglomeration of drug particles after exposure to the dissolution medium [28]. PEGs can also act as surface active agents and facilitate wetting of the drug particles by decreasing the interfacial tension between the dissolution medium and the drug. Additionally, these carriers (PEG 4000 and PEG 6000) are able to inhibit the crystal growth of phenytoin which can lead to the facilitated dissolution [32]. The results of these processes are clearly observed by comparing the dissolution parameters such as D5min (percent of drug dissolved in dissolution medium after 5 min) and T50% (the time required for dissolving 50% of the drug in the dissolution medium). For example, D5min for cogrinds made from PEG 2000, PEG 6000 and PEG 20000 with the ratios of drug:PEG 1:1 and 1:10 at pH 6.8 is 91, 65, 55% and 99, 97, 93%, respectively. These results show that the differences in dissolution rates between various PEGs are more obvious in the low drug:PEG ratio.
4. Particle size analysis
The results of the particle size analysis for pure drug powder and treated samples showed slight changes in the particle size diameter and total surface area after the grinding process. The median particle diameter of pure drug powder and treated samples was 21.47 and 16.98 µm and the surface area was 0.181 and 0.214 mm2/g, respectively. These results showed that the cogrinding process did not substantially reduce the particle size of indomethacin and, hence, this process alone could not profoundly increase the dissolution rate of indomethacin in the dissolution media. The results of particle size measurements could also describe the small difference between dissolution profiles of pure drug powder and samples.
5. Influence of the drug/PEG ratio
As shown in Figures 2 to 4, an increase in the concentration of PEG in the cogrinds formulations resulted in an increase in the dissolution 24
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Figure 5 shows the dissolution profiles of indomethacin from pure drug powder, treated pure drug, physical mixtures and cogrinds at pH 6.8 up to 10 min. As shown in this figure, there is no significant difference between the dissolution of indomethacin from cogrinds made from different ratios of the drug:PEG 2000 whereas in the case of drug: PEG 20000 significant differences are observed. This indicates that molecular weight of PEG is also an important factor in controlling the dissolution rate of indomethacin. The differences between D5min of cogrinds with the ratios of 1:1 and 1:10 drug:PEG were 37.75, 31.77 and 8.01%, for PEG 20000, PEG 6000 and PEG 2000, respectively. Table I shows that the major mechanism in increasing the dissolution rate of indomethacin by PEG 20000 and probably other long chain PEGs could be related to the ability of these carriers to increase the indomethacin solubility. In the case of PEG 2000, increasing the carrier-drug ratio cannot substantially affect the dissolution rate of the drug. As the melting point of PEG 2000 is relatively low (45-50°C), this carrier is able to form a film around the drug particles by melting or softening of the polymer during the cogrinding process. The friction resulting from the cogrinding process could generate the heat required
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Figure 4 - Dissolution profiles of indomethacin from different formulations: (X) pure drug powder; (+) treated pure drug; physical mixtures with ratios of (●) 1:1, (◆)1:2, (■)1:5, (▲)1:10 and solid dispersions with (O)1:1, (◊)1:2, (❐)1:5, (Δ) 1:10 drug:polymer prepared with (A)PEG 2000, (B) PEG6000 and (C) PEG20000 at pH 1.2.
Table I - The indomethacin solubility enhancement ratios (ERs) in presence of PEG 2000, PEG 6000 and PEG 20000 with different concentrations (mg/100 ml) at different pHs (n = 3). pH 1.2 4.6 6.8
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1.76 1.89 2.22
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1.98 1.82 2.11
2.36 2.58 2.87
3.00 3.41 4.04
4.38 4.77 4.84
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Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights J. Shokri, J. Hanaee, M. Barzegar-Jalali, R. Changizi, M. Rahbar, A. Nokhodchi
for melting or softening of a low melting point carrier, such as PEG 2000. This was also confirmed by Craig and Newton [33] who studied the melting behaviour of the ground samples of PEG with different molecular weights using differential scanning calorimetry (DSC). It was demonstrated that the shape of the endotherm was sensitive to the sample particle size and the molecular weight of PEG . They showed that for low molecular weight PEG there were changes in thermal behaviour due to grinding of PEG powders. However, no changes were observed for the ground PEG 20000 samples (high molecular weight). This could be attributed to the low melting point of low molecular weight PEG which is able to form a film around the drug particles by melting or softening the polymer during the grinding process (changes from glassy to rubbery state). The drug/carrier ratio of 1:1 for PEG 2000 in the cogrind might be enough to coat the drug particles and, hence, an increase in carrier concentration beyond 1:1 is not able to further enhance the dissolution rate of indomethacin. The greater differences between the dissolution rates of physical mixtures and cogrinds made from indomethacin and PEG 2000 in comparison with other higher molecular weight PEGs, such as PEG 20000, indicates that the cogrinding process is more effective in dissolution enhancement of indomethacin in cogrinds formulations containing low molecular weight polymers (Figure 2), especially when the drug:carrier ratio is low. It has been shown that the release rate is inversely proportional to the chain length of the PEG [7]. Similar results have been obtained with etoposide [34] and griseofulvin [35]. However, other studies revealed contradictory behaviour. For example, glyburide release from a solid
J. DRUG DEL. SCI. TECH., 16 (3) 203-209 2006
dispersion in PEG 6000 (ratio of drug: PEG was 1:8) was faster than from a similar dispersion in PEG 4000 [28]. Possible reasons suggested for the better release from PEG 6000 were that the PEG 6000 was able to dissolve more of the drug than the PEG 4000, leading to a greater percentage of drug in the molecularly dispersed form, and that the higher viscosity of the PEG 6000 hindered precipitation of the drug following dissolution of the carrier. In yet other cases, the molecular weight of the PEG had no influence at all on the release rate [36]. Table I shows the solubility enhancement ratios (ER) of indomethacin produced by various PEGs with different concentrations. As shown in this table, the highest ER was observed for the highest molecular weight PEGs (PEG 20000), when considering the same concentration. The ER values were directly proportional to the chain length of the carrier PEG . The indomethacin solubility enhancement, based on the modified Noyes-Whitney equation, can increase the dissolution rate of the drug. The dissolution profiles also reveal the higher dissolution rates of indomethacin from cogrinds made with high molecular weight PEGs compared with those made with low molecular weight PEGs. Figure 5 shows the dissolution profiles of the drug from cogrinds and physical mixtures made from various PEGs with a 1:1 drug:PEG ratio at various pHs. The dissolution of indomethacin from cogrinds at pH 6.8 shows a reverse correlation with the molecular weight of polymers. This relationship is evident with the slower dissolution rate with high molecular weight PEG , compared with low molecular weight PEGs. In the early stages, PEG 20000 does not dissolve completely in the dissolution medium and, 120
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Figure 5 - Dissolution profiles of indomethacin (0 to 10 min) from different formulations: (X) pure drug powder; (+) treated pure drug; physical mixtures with ratios of (●) 1:1, (◆)1:2, (■)1:5, (▲)1:10 and solid dispersions with (O)1:1, (◊)1:2, (❐)1:5, (Δ) 1:10 drug:polymer prepared with (A)PEG 2000, (B) PEG6000 and (C) PEG20000 at pH 6.8.
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J. DRUG DEL. SCI. TECH., 16 (3) 203-209 2006
Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights J. Shokri, J. Hanaee, M. Barzegar-Jalali, R. Changizi, M. Rahbar, A. Nokhodchi
hence, cannot increase the dissolution rate of indomethacin in the medium by an enhanced solubility mechanism.
11.
7. Effects of dissolution media
12.
Comparing the results of dissolution profiles for different PEGs at various pHs show that pH has a substantial effect on the dissolution rate of indomethacin from cogrind formulations. It has already been shown that solid dispersions made with lower molecular weight PEG 2000 produced a faster dissolution rate at pH 6 than those made with higher molecular weight PEG 20000. The results at lower pHs such as pH 4.6 and 1.2 showed that the highest dissolution rate of indomethacin was observed for cogrinds containing the highest molecular weight of PEG (PEG 20000). At these pHs, a direct proportionality between the dissolution rate of indomethacin and molecular weight of PEGs is seen (Figure 6). It seems that the dominant mechanism for controlling the dissolution rate of the drug by PEG at pH 6.8 is the viscosity of the diffusion layer, whereas in the more acidic media (pH 4.6 and 1.2), the solubility enhancement effect of PEG plays the more significant role in the dissolution enhancement of the drug. These results also showed that the acidity of dissolution media could greatly influence the dissolution behaviors of indomethacin in the cogrinds. This could be due to the faster dissolution of PEG 2000 than PEG 6000 and PEG 20000 at higher pH 6.8 [23, 27]. Another reason for the lower dissolution rate of indomethacin from cogrinds containing higher molecular weight of PEGs at pH 6.8 may be due to a reduction in the diffusion coefficient as a result of higher viscosity of the diffusion layer produced by the higher molecular weight PEGs [23].
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REFERENCES 1. 2. 3.
4.
5. 6.
7. 8.
9.
10.
19.
KERC J., SRCIC S., KNEZ Z. and SENCAR-BOZIC P.- Micronization of drugs using supercritical carbon dioxide. - Int. J. Pharm., 182, 33-39, 1999 MURA P., FAUCCI T.M. and BETTINETTI G.P.- The influence of polyvinylpyrrolidone on naproxen complexation with hydroxypropyl-β-cyclodextrin. - Eur. J. Pharm. Sci., 13, 187-194, 2001 MURA P., BETTINETTI G.P. and FUCCI T.M. - Interaction of naproxen with crystalline and amorphous methylated beta-cyclodextrin in the liquid and solid state. - Supramol. Chem., 12, 379-389, 2001. BETTINETTI G.P., MURA P., FUCCI M.T, SORRENTI M. and SETTI M. - Interaction of naproxen with noncrystalline acetyl β- and acetyl γ-cyclodextrins in the solid and liquid state. - Eur. J. Pharm. Sci., 15, 21-29, 2002. NYSTROM C. and WESTERBERG M. - Use of ordered mixtures for improving the dissolution rate of low solubility compounds. - J. Pharm. Pharmacol., 38, 161-165, 1986. BARZEGAR-JALALI M., MALEKI N., GARJANI A., KHANDAR A.A., HAJI-HOSSEINLOO M., JABBERI R. and DASMALCHI S. - Enhancement of dissolution rate and anti-inflammatory effects of piroxicam by solvent deposition technique. - Drug Dev. Ind. Pharm., 28, 681-686, 2002. FORD J.L. - The current status of solid dispersions. - Pharm. Acta Helv., 61, 69-88, 1986. VERHEYEN S., BLATON N., KINGEST R. and VAN DEN MOOTER G. - Mechanism of increased dissolution of diazepam from polyethylene glycol 6000 solid dispersions. - Int. J. Pharm., 249, 45-58, 2002. VALIZADEH H., NOKHODCHI A., QARAKHANI N., ZAKERI-MILANI P., AZARMI Sh., HASSAN-ZADEH D. and LOEBENBERG R. - Physicochemical characterization of solid dispersions of indomethacin with PEG 6000, Myrj 52, lactose, sorbitol, dextrin, and Eudragit1 E100. - Drug Dev. Ind. Pharm., 30, 303-317, 2004. NOZAWA Y., MIZUMOTO T. and HIGASHIDE F. - Improving dissolution rates of practically insoluble drug phenytoin by roll mixing with polyvinyl pyrrolidone. - Pharm. Acta Helv., 60, 175177, 1985.
20.
21. 22. 23.
24.
25.
26.
27.
28.
208
CANAL T., LOVERCICH M. and RUBESSA F. - Effect of coprecipitation of phenylbutazone with poly(vinylmethylether/maleic anhydride) on its dissolution behavior. - Pharmazie, 44, 619-621, 1989. FERNANDEZ M., RODRIGUEZ I.C., MARGARIT M.V. and CEREZO A. - Characterization of solid dispersions of piroxicam/polyethylene glycol 4000. - Int. J. Pharm., 84, 197-202, 1992. MURA P., ZEROUK N., MENNINI N., MAESTRELLI F. and CHEMTOB C. - Development and characterization of naproxenchitosan solid systems with improved drug dissolution properties. - Eur. J. Pharm. Sci., 19, 67-75, 2003. SUGIMOTO M., OKAGAKI T., NARISAWA S., KOIDA Y. and NAKAJIMA K. - Improvement of dissolution characteristics and bioavailability of poorly water-soluble drugs by novel cogrinding method using water-soluble polymers. - Int. J. Pharm., 160, 1119, 1998. VAN DER MOOTER G., WUYTS M., BLATON N., BUSSON R., GROBET P., AUGUSTIJNS P. and KINGEST R. - Physical stabilization of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. - Eur. J. Pharm. Sci., 12, 261-269, 2001. ZERROUK N., CHEMTOB C., ARNAUD P., TOSCANI S. and DUGUE J. - In vitro and in vivo evaluation of carbamazepine-PEG 6000 solid dispersions. - Int. J. Pharm., 225, 49-62, 2001. OZEKI T., YUASA H. and KANAYA Y. - Control of medicine release from solid dispersion composed of the poly(ethylene oxide)-carboxyvinylpolymer interpolymer complex by varying molecular weight of poly(ethylene oxide). - J. Controlled Release., 58, 87-95, 1999. OZEKI T., YUASA H. and KANAYA Y. - Controlled release from solid dispersion composed of poly(ethylene oxide)-Carbopol(r) interpolymer complex with various cross-linking degrees of Carbopol(r). - J. Controlled Release., 63, 287-295, 2000. EMAS M. and NYQVIST H. - Methods of studying aging and stabilization of sprayed-congealed solid dispersions with carnuba wax. 1. Micro calorimetric investigation. - Int. J. Pharm., 197, 117-127, 2000. GINES J.M., ARIAS M.J., MOYANO J.R. and SANCHEZ-SOTO P.J. - Thermal investigation of crystallization of polyethylene glycols in solid dispersions containing oxazepam. - Int. J. Pharm., 143, 247-253, 1996. SHIN S.C. and KIM J. - Physicochemical characterization of solid dispersion of furosemide with TPGS. - Int. J. Pharm., 251, 79-84, 2003. TANTISHAIYAKUL V., KAEWNOPPARAT N. and INGKATAWORNWONG S. - Properties of solid dispersions of piroxicam in polyvinylpyrrolidone K30. - Int. J. Pharm., 25, 29-66, 1996. ARIAS M.J., GINES J.M, MOYANO J.R. and RABASCO A.M. - Dissolution properties and in vivo behavior of triamterene in solid dispersions with polyethylene glycols. - Pharm. Acta Helv., 71, 229-235, 1996. OZEKI T., YUASA H. and KANAYA Y. - Application of the solid dispersion method to the controlled release of medicine. IX. Difference in the release of flurbiprofen from solid dispersions with poly(ethylene oxide) and hydroxypropylcellulose and the interaction between medicine and polymer. - Int. J. Pharm., 155, 209-217, 1997. LIN S.Y., CHIEN K.S. and TENG H.H. - Protective colloids and polylactic acid co-affecting the polymorphic crystal forms and crystallinity of indomethacin encapsulated in microspheres. - J. Microencapsulation., 16, 769-776, 1999. OTSUKA M., KATO F. and MATSUDA Y. - Determination of indomethacin polymorphic contents by chemometric near-infrared spectroscopy and conventional X-ray diffractometry. - Analyst, 126, 1578-1582, 2001. SPYCHALA S., BUTKIEWICZ K., PAKULA R. and PICHNEJ L. - Polymorphism of indomethacin: Part II. Identification and rapid determination of polymorphic forms of indomethacin by IR spectroscopy. - J. Pharmacol. Pharm., 29, 157-161, 1977. BETAGERI G.V. and MAKARLA K.R. - Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques. - Int. J. Pharm., 126, 155-160, 1995.
Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights J. Shokri, J. Hanaee, M. Barzegar-Jalali, R. Changizi, M. Rahbar, A. Nokhodchi
29.
30.
31. 32.
33. 34. 35.
TRAPANI G., FRANCO M., LATROFA A., PANTALEO M.R., SANNA E., MACIOCCO E. and LISO G. - Physicochemical characterization and in vivo properties of Zolpidem in solid dispersions with polyethylene glycol 4000 and 6000. - Int. J. Pharm., 184, 121-130, 1999. GUYOT M., FAWAZ F., BILDET J., BONINI F. and LEGUENY A.M. - Physicochemical characterization and dissolution of norfloxacin/cyclodextrin inclusion compounds and solid dispersions. - Int. J. Pharm., 123, 53-63, 1995. ÖZKANY., DOGANAY N., DIKMEN N. and ISIMER A. - Enhanced release of solid dispersions of etodolac in polyethylene glycol. - Farmaco., 55, 433-438, 2000. SEKIKAWA H., NAANUMA T., FUJIWARA, J., NAKANO M. and ARITA T. - Dissolution behaviors and gastrointestinal absorption of phenytoin in phenytoin-PVP coprecipitate. - Chem. Pharm. Bull., 27, 1223-1230, 1979. CRAIG D.Q.M., NEWOTON J.M.- Characterisation of polyethylene glycols using differential Scanning calorimetry.- Int. J. Pharm., 74, 31-41, 1991. SHAH J.C. and CHEN J.R. - Chow D. Preformulation study of etoposide. II. increased solubility and dissolution rate by solidsolid dispersions. - Int. J. Pharm., 113, 103-111, 1995. CHIOU W.L. and RIEGELMAN S. - Preparation and dissolu-
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36.
37.
tion characteristics of several fast-release solid dispersions of griseofulvin. - J. Pharm. Sci., 58, 1505-1510, 1969. MURA P., FAUCCI T.M., MANDERIOLI G., BRAMANTI P. and PARRINI P. - Thermal behaviour and dissolution properties of naproxen from binary and ternary solid dispersions. - Drug Dev. Ind. Pharm., 25, 257-264, 1999. CORRIGAN O.I. - Retardation of polymeric carrier dissolution by dispersed drugs: factors influencing the dissolution of solid dispersions containing polyethylene glycols. - In: Pharmaceutical Technology: Controlled Drug Release,M.H. Rubinstein Ed., Ellis Horwood Limited, Chichester, 1987, pp. 88-98.
ACKNOWLEGEMENT We would like to thank Dr Taravat Ghafourian for useful discussion and comments.
MANUSCRIPT Received 28 October 2005, accepted for publication 24 March 2006.
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Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights J. Shokri1, J. Hanaee2, M. Barzegar-Jalali3, R. Changizi2, M. Rahbar2, A. Nokhodchi3, 4* Research Center of Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran 2 School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran 3 Drug Applied Research Center (DARC), Tabriz University of Medical Sciences, Tabriz, Iran 4 Medway School of Pharmacy, The University of Kent and Greenwich, Central Avenue, Chatham Maritime, Kent, ME4 4TB, United Kingdom *Correspondence: [email protected] or [email protected]
1
Indomethacin is an anti-inflammatory drug which is used to relieve pain and inflammatory conditions. For poorly soluble drugs and highly permeable drugs such as indomethacin, the rate of oral absorption is often controlled by the dissolution rate in the gastrointestinal tract. Therefore together with the permeability, the solubility and dissolution behaviour of a drug are key determinants of its oral bioavailability. In this study, an attempt was made to enhance the dissolution rate of indomethacin using various molecular weights of polyethylene glycol (PEG 2000, 6000 and 20000) by a cogrinding technique. The cogrinds containing different drug:PEG ratios (1:1, 1:2, 1:5, 1:10) were made and the dissolution rate of the drug from each of the formulations was studied at different pHs (1.2, 4.6 and 6.8). The results showed a significant increase in the dissolution rate of indomethacin at various pHs from cogrinds formulations, obtained by this cogrinding technique, in comparison to that of the pure drug powder, treated pure drug, or physical mixtures at all studied pHs. The dissolution results did not show significant differences between the dissolution rates of indomethacin from cogrinds containing PEG 2000 with various drug:carrier ratios, whereas these differences were considerably significant for the cogrinds samples containing PEG 20000. These results confirm that the dominant mechanism of low molecular weights of PEG s in increasing the indomethacin dissolution rate from cogrinds is the formation of a thin film of the PEG around the poorly soluble drug particles. In the case of high molecular weight PEGs, such as PEG 20000, since the indomethacin:carrier ratios significantly affected the dissolution rate of indomethacin from the cogrinds, therefore, it seems that the increase in dissolution of indomethacin from these cogrinds was mainly caused by an improved solubility of the drug by the presence of these carriers. The particle size analysis showed small changes in the particle size diameter and powder surface area of indomethacin after grinding (16.3% reduction in median particle diameter and 18.8% increase in the total powder surface area). The XRD and FTIR spectra rejected any polymorphic changes or the production of amorphous indomethacin due to the cogrinding process. These spectra showed only slight changes in the crystal orientation after milling. Key words: Cogrinds – Indomethacin – Dissolution rate – Cogrinding – Physical mixtures – Polyethylene glycols.
Indomethacin ([1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid) is an analgesic, antipyretic and non-steroidal anti-inflammatory drug (NSAID) which is used to relieve pain and inflammatory conditions. Indomethacin is practically insoluble in water and, thus, very slowly dissolves in gastrointestinal fluids. The dissolution rate of poorly water-soluble drugs, such as indomethacin, is one of the most important properties that can greatly influence the therapeutic effect of formulations, especially in the case of drugs that are easily absorbed from the gastrointestinal tract (class II drugs). As the absorption of the poorly soluble drugs from the gastrointestinal tract is limited by the dissolution rate, they often show low bioavailability when administered orally. Therefore, it is important to enhance their dissolution rate. Several methods have been used to improve the dissolution rate of poorly water-soluble drugs such as micronization [1], complexation [2-4], ordered mixture [5], solvent deposition [6], solid dispersion [7-9] and roll mixing [10]. Some of these methods have been applied to the production of pharmaceutical preparations. Among these methods, the solid dispersion techniques are the most effective methods for this purpose. Traditionally, solid dispersions are prepared by coprecipitation [11], coevaporation [4], melting [12] or cogrinding [13, 14] methods. Soluble carriers, such as polyvinyl pyrrolidones, [15], polyethylene glycols (PEGs), [8, 16], hydroxypropylmethylcellulose, [14] carboxy vinyl polymers [17, 18] and carnauba wax, [19] have been used in the preparation of solid dispersions. It has been shown that the dissolution rate of poorly water-soluble drugs, such as diazepam [8], oxazepam [20], furosemide [21], nifedipine [14], carbamazepine [16], piroxicam [32], triamteren [23], indomethacin
[9] and griseofulvin, [14] can be increased by using solid dispersion techniques. The solid dispersion of drugs with hydrophobic carriers, such as Eudragit RL and RS, has been used for preparation of sustained release formulations[17, 24]. In the present study, the dissolution rate of indomethacin from cogrinds made from different polyethylene glycols (PEG 2000, 6000 and 20000) at different pHs (1.2, 4.6 and 6.8) was investigated. Cogrinds with various ratios of drug:PEG were made using a cogrinding method and the dissolution rate of indomethacin from each of them was determined in different dissolution media.
I. MATERIALS AND METHODS
Indomethacin powder was provided by Zahravi Pharmaceutical (Tabriz, Iran). PEG 2000, PEG 6000, PEG 20000 and sodium oleate were purchased from Merck Chemical Co. (Darmstadt, Germany).
1. Preparation of samples
Pure indomethacin powder and each of the PEGs were mixed and charged into the chamber of a vibration ball mill (Fritsch, Utzenhofen, Germany) with various drug-PEGs ratios (1:1, 1:2, 1:5 and 1:10). A certain number of steel balls were added in a way that the total volume of powder mixture and balls equaled one-third the volume of the ball mill chamber. The powder mixtures were ground 3 h at a vibration speed 360 rpm. Then, the samples were collected and the dissolution rate of indomethacin from each of the formulations was measured. For preparation of treated pure drug samples, the drug powders were ground alone in the ball mill under the same conditions used to prepare the cogrinds. Physical mixtures of drug:PEGs were prepared by simple 203
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Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights J. Shokri, J. Hanaee, M. Barzegar-Jalali, R. Changizi, M. Rahbar, A. Nokhodchi
mixing of the drug powder and each of PEGs with the same ratios that have been used for cogrind formulations. The mass of selected samples for the dissolution study was 25 mg for pure drug powder and treated pure drug, and 50, 75, 125 and 275 mg for cogrinds and physical mixtures formulations with 1:1, 1:2, 1:5, 1:10 drug:PEGs ratios, respectively, such that each sample contained 25 mg indomethacin.
6. Particle size analysis
Median particle size, powder surface area and particle size distribution for the pure drug powder and treated pure drug samples were determined by using a centrifugal particle size analyzer (Shimadzu SA-CP3, Tokyo, Japan) at 2200 rpm with step size of 120 rpm/min. The samples were prepared by adding the suitable amount of the drug powder in water containing sodium oleate as suspending agent. The viscosity of the samples was also measured by a Brookfield LVDVII+ viscometer before particle sizing.
2. Dissolution studies
The dissolution of indomethacin from cogrinds, physical mixtures, untreated pure drug powders and treated pure drug were measured at least in triplicate using a USP 24 standard dissolution apparatus II at 100 rpm (Erweka DT 6R, Heusenstamm, Germany). The dissolution medium was 900 ml of different pH values (1.2, 4.6 and 6.8), which was maintained at 37°C. Samples equivalent to 25 mg of indomethacin was added to 900 ml of dissolution media. At suitable time intervals (5, 10, 15, 30, 60, 120, 240, 360, 480 and 600 min), 5-ml samples were withdrawn and replaced with equal volumes of fresh dissolution media. The concentration of indomethacin in these samples was determined by UV-Visible spectrophotometry (Shimadzu mini 1240, Tokyo, Japan) at 266.5 nm.
II. RESULTS AND DISCUSSION 1. XRD and FT-IR studies
Diffraction spectra of physical mixtures and cogrinds of indomethacin-PEG showed that there were no changes in the spectrum of physical mixtures and coground formulations. For example, the XRD of the physical mixtures of PEG 2000 or PEG 20000 with indomethacin and their coground formulations are shown in Figure 1. The figure shows that each of the principal peaks observed with physical mixtures was present in their respective cogrinds, although with different intensities, and that there was no new peak associated with the cogrinds suggesting the existence of an interaction between the drug and the carrier. Furthermore, the x-ray diffraction patterns of the samples also did not show any polymorphic changes in the samples. The pattern of XRD results of the treated (pure drug powder and cogrinds) and untreated (pure drug powder and physical mixtures) samples demonstrated high similarities to the pattern described in previous studies for the γ polymorph of indomethacin [9, 25, 26]. These include peaks located at 10.2, 11.6, 17.0, 19.6, 20.8, 21.8, 24.0, 26.2 and 29.5° for the γ polymorph of indomethacin. The change in the intensity of indomethacin peaks observed in cogrinds samples as compared to their respective physical mixtures could be due to the change of the crystal orientation during the analysis. In other words, the results indicate that the crystalline nature of the drug in the cogrinds is essentially maintained, but the size of the crystals might have been reduced. The positions of the peaks for the physical mixtures and cogrinds for samples involving the different PEGs were the same and superimposable, which again ruled out the possibility of chemical interaction and compound formation between these two components. FT-IR spectra were used to further characterize the possibility of interactions between indomethacin and PEGs in the solid state. From the structures of indomethacin and PEG it can be assumed that possible interaction could occur between the carboxyl group of indomethacin and the hydroxyl group of PEG . In this case any sign of interaction would be reflected by a change in the O-H vibration, depending on
3. Solubility measurements
Solubility measurements were performed in order to determine the effects of pH, as well as the molecular weight and concentration of the PEGs, on the solubility of indomethacin in these media. To accomplish this, an excess amount of the drug powder was added to 50 ml of the dissolution media with or without a PEG present. The concentrations of PEGs used in the solubility measurements were exactly the same concentrations used in the dissolution studies (0.025, 0.05, 0.125 and 0.25 mg/ml for 1:1, 1:2, 1:5 and 1:10 drug-PEGs ratios, respectively). The solubility tests were performed in triplicate. The drug suspensions with or without PEGs was shaken for 24 h (this duration was previously tested to be sufficient to reach equilibrium) at 37 ± 0.5°C (Heidolph, Incubator 1000, Schwabach, Germany). Subsequently, the samples were filtered through Ashless No. 41 Whatman filter paper (Maidstone, UK) and assayed at the wavelength of 266.5 nm after suitable dilution. After determining the solubility of indomethacin at different pHs in the presence of various PEGs, the solubility enhancement ratio (ER) (solubility of indomethacin in solutions containing a definite concentration of PEG/solubility of indomethacin in the same dissolution media without the PEG) was determined for each concentration of the tested PEG.
4. X-ray diffractometry (XRD)
XRD was used to determine the changes in the crystallinity of indomethacin in the samples during the cogrinding process. Powder X-ray diffraction patterns of samples were recorded using a Zeimens T5000 diffractometer (Munich, Germany) with Ni filtered CuKα line as the source of radiation (40 Kv, 30 mA). The angular range 2-40 2θ was scanned with a step size of 0.02° 2θ at the rate of 1°/min. These spectra were prepared for pure drug powder, treated pure drug, physical mixtures and coground drug-PEG samples at 1:1 ratios in 1.5406 Å wavelength, and the 2θ values of the peaks were compared.
5. Fourier transform infrared (FT-IR) spectroscopy
FT-IR spectra were used to investigate polymorphic changes during the grinding process. These spectra were taken by Bomem MB100 FT-IR series (Quebec, Canada) equipment for untreated pure drug powder, treated pure drug, physical mixtures and cogrinds. The cogrinds and physical mixtures with a 1:1 drug-PEG ratio were chosen for the FT-IR studies. Samples were mixed with KBr powder and compressed to 10-mm discs by a hydraulic press at a pressure of 10 tons for 30 s. The scanning range was 450-4000 cm-1 and the resolution was 2 cm-1.
Figure 1 - XRD of (A) physical mixtures of indomethacin-PEG 2000, (B) coground indomethacin-PEG 2000, (C) physical mixture of indomethacin-PEG 20000, (D) coground indomethacin-PEG 20000.
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the extent of interaction. The FT-IR spectra did not show any interaction between indomethacin and PEG in the coground samples. The main identifying peaks in the FT-IR spectrum of indomethacin were described previously by Spychala et al. [27] for determining the type of indomethacin polymorphs. All of the FT-IR spectra for tested samples showed the peaks similar to that described for the γ form of indomethacin (γ = 1,692 and 1,716 cm-1) in the previous articles. In conclusion, the results of the FT-IR and XRD analyses showed that indomethacin did not undergo any polymorphic changes during the cogrinding process and essentially maintained the initial crystalline structure during and after grinding in the absence or presence of various PEGs.
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[28], an increased wettability of the drug particles [28, 29] and an increase in the solubility of the drug [29, 30]. The X-ray diffraction patterns and FT-IR spectra rejected any changes in the indomethacin crystalline structure. The small difference between the dissolution rates of indomethacin from pure drug and from treated pure drug indicates that the cogrinding process could slightly increase the dissolution rate of treated drug even in the absence of PEG (see Figures 2 to 4). The effects of many different factors on the dissolution rate of indomethacin from physical mixtures and cogrinds have been studied and the results are described below.
3. Effect of PEG on the solubility of indomethacin
Table I shows the ER of various molecular weights of PEGs with different concentrations at different pHs. It can be seen in this table that, at the same concentrations of PEG, the samples containing higher molecular weight PEG have higher ER values at different pHs. The ER values also directly correlated with the concentrations of the PEGs. The highest ER value (4.8) was observed for the highest concentration (250 mg/l) of PEG 20000 at pH 6.8. Moreover, the results showed that the pH of dissolution media did not considerably alter the ER values in the presence of PEG . However, the solubility of indomethacin is greatly affected by the pH of the dissolution media in the absence of PEG, equal to 2.1, 13.2 and 27.5 µg/ml at pH 1.2, 4.6 and 6.8, respectively.
2. Dissolution studies
The effects of many different factors on the dissolution rate of indomethacin from physical mixtures and cogrinds have been studied and the results are described below. The results of the dissolution tests at different pHs are shown in Figures 2 to 4. As shown in these figures, each of the coground formulations exhibited a substantially higher dissolution rate than the pure drug powder or the physical mixtures with the same drug-polymer ratio at the same pH. Several mechanisms have been postulated for an increase in the dissolution rate of drugs from cogrinds containing hydrophilic polymers, such as the PEGs. Some of the suggested mechanisms include micronization
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Figure 3 - Dissolution profiles of indomethacin from different formulations: (X) pure drug powder; (+) treated pure drug; physical mixtures with ratios of (●) 1:1, (◆)1:2, (■)1:5, (▲)1:10 and solid dispersions with (O)1:1, (◊)1:2, (❐)1:5, (Δ) 1:10 drug:polymer prepared with (A)PEG 2000, (B) PEG6000 and (C) PEG20000 at pH 4.6.
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rate of indomethacin. For instance, the percentage indomethacin dissolved after 5 min from the cogrind samples with the ratios of drug:PEG 20000 1:1, 1:2, 1:5 and 1:10 were approximately 55, 72, 82 and 93% at pH 6.8 (Figure 2C). Similar results can be ruled out for the cogrind samples containing PEG 2000 and 6000 at pH 1.2 or 4.6 (Figures 3 and 4). The correlation between a hydrophilic carrier concentration and the dissolution rate of various drugs from solid dispersions has been observed in other investigations [23, 28, 31]. The drug/carrier ratio in a solid dispersion is one of the main factors affecting the performance of a solid dispersion. It has been shown that if the percentage of the drug were too high (high ratio of drug/carrier), it would form small crystals within the dispersion rather than remaining molecularly dispersed. On the other hand, if the percentage of the carrier were very high (low ratio of drug/carrier), this could lead to the complete absence of crystallinity of the drug and thereby enormous increases in the solubility (see Table I) and dissolution rate of the drug. This could be the reason for the observed increase in the solubility (see Table I) of indomethacin and consequently, the dissolution rate of indomethacin with the increase in the concentration of PEG. An increase in the amount of PEG can also enhance the hydrophilicity of the surface of the solid dispersion particles and this, in turn, reduces the agglomeration of drug particles after exposure to the dissolution medium [28]. PEGs can also act as surface active agents and facilitate wetting of the drug particles by decreasing the interfacial tension between the dissolution medium and the drug. Additionally, these carriers (PEG 4000 and PEG 6000) are able to inhibit the crystal growth of phenytoin which can lead to the facilitated dissolution [32]. The results of these processes are clearly observed by comparing the dissolution parameters such as D5min (percent of drug dissolved in dissolution medium after 5 min) and T50% (the time required for dissolving 50% of the drug in the dissolution medium). For example, D5min for cogrinds made from PEG 2000, PEG 6000 and PEG 20000 with the ratios of drug:PEG 1:1 and 1:10 at pH 6.8 is 91, 65, 55% and 99, 97, 93%, respectively. These results show that the differences in dissolution rates between various PEGs are more obvious in the low drug:PEG ratio.
4. Particle size analysis
The results of the particle size analysis for pure drug powder and treated samples showed slight changes in the particle size diameter and total surface area after the grinding process. The median particle diameter of pure drug powder and treated samples was 21.47 and 16.98 µm and the surface area was 0.181 and 0.214 mm2/g, respectively. These results showed that the cogrinding process did not substantially reduce the particle size of indomethacin and, hence, this process alone could not profoundly increase the dissolution rate of indomethacin in the dissolution media. The results of particle size measurements could also describe the small difference between dissolution profiles of pure drug powder and samples.
5. Influence of the drug/PEG ratio
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Figure 4 - Dissolution profiles of indomethacin from different formulations: (X) pure drug powder; (+) treated pure drug; physical mixtures with ratios of (●) 1:1, (◆)1:2, (■)1:5, (▲)1:10 and solid dispersions with (O)1:1, (◊)1:2, (❐)1:5, (Δ) 1:10 drug:polymer prepared with (A)PEG 2000, (B) PEG6000 and (C) PEG20000 at pH 1.2.
Table I - The indomethacin solubility enhancement ratios (ERs) in presence of PEG 2000, PEG 6000 and PEG 20000 with different concentrations (mg/100 ml) at different pHs (n = 3). pH 1.2 4.6 6.8
PEG 2000
PEG 6000
PEG 20000
25
50
125
250
25
50
125
250
25
50
125
250
1.19 1.14 1.31
1.52 1.59 1.89
1.95 1.97 3.05
3.07 2.38 3.64
1.44 1.36 1.67
1.76 1.89 2.22
2.33 2.50 3.38
3.52 3.41 4.07
1.98 1.82 2.11
2.36 2.58 2.87
3.00 3.41 4.04
4.38 4.77 4.84
206
Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights J. Shokri, J. Hanaee, M. Barzegar-Jalali, R. Changizi, M. Rahbar, A. Nokhodchi
for melting or softening of a low melting point carrier, such as PEG 2000. This was also confirmed by Craig and Newton [33] who studied the melting behaviour of the ground samples of PEG with different molecular weights using differential scanning calorimetry (DSC). It was demonstrated that the shape of the endotherm was sensitive to the sample particle size and the molecular weight of PEG . They showed that for low molecular weight PEG there were changes in thermal behaviour due to grinding of PEG powders. However, no changes were observed for the ground PEG 20000 samples (high molecular weight). This could be attributed to the low melting point of low molecular weight PEG which is able to form a film around the drug particles by melting or softening the polymer during the grinding process (changes from glassy to rubbery state). The drug/carrier ratio of 1:1 for PEG 2000 in the cogrind might be enough to coat the drug particles and, hence, an increase in carrier concentration beyond 1:1 is not able to further enhance the dissolution rate of indomethacin. The greater differences between the dissolution rates of physical mixtures and cogrinds made from indomethacin and PEG 2000 in comparison with other higher molecular weight PEGs, such as PEG 20000, indicates that the cogrinding process is more effective in dissolution enhancement of indomethacin in cogrinds formulations containing low molecular weight polymers (Figure 2), especially when the drug:carrier ratio is low. It has been shown that the release rate is inversely proportional to the chain length of the PEG [7]. Similar results have been obtained with etoposide [34] and griseofulvin [35]. However, other studies revealed contradictory behaviour. For example, glyburide release from a solid
J. DRUG DEL. SCI. TECH., 16 (3) 203-209 2006
dispersion in PEG 6000 (ratio of drug: PEG was 1:8) was faster than from a similar dispersion in PEG 4000 [28]. Possible reasons suggested for the better release from PEG 6000 were that the PEG 6000 was able to dissolve more of the drug than the PEG 4000, leading to a greater percentage of drug in the molecularly dispersed form, and that the higher viscosity of the PEG 6000 hindered precipitation of the drug following dissolution of the carrier. In yet other cases, the molecular weight of the PEG had no influence at all on the release rate [36]. Table I shows the solubility enhancement ratios (ER) of indomethacin produced by various PEGs with different concentrations. As shown in this table, the highest ER was observed for the highest molecular weight PEGs (PEG 20000), when considering the same concentration. The ER values were directly proportional to the chain length of the carrier PEG . The indomethacin solubility enhancement, based on the modified Noyes-Whitney equation, can increase the dissolution rate of the drug. The dissolution profiles also reveal the higher dissolution rates of indomethacin from cogrinds made with high molecular weight PEGs compared with those made with low molecular weight PEGs. Figure 5 shows the dissolution profiles of the drug from cogrinds and physical mixtures made from various PEGs with a 1:1 drug:PEG ratio at various pHs. The dissolution of indomethacin from cogrinds at pH 6.8 shows a reverse correlation with the molecular weight of polymers. This relationship is evident with the slower dissolution rate with high molecular weight PEG , compared with low molecular weight PEGs. In the early stages, PEG 20000 does not dissolve completely in the dissolution medium and, 120
Percent dissolved
Percent dissolved
120
A
100 80 60 40 20
100 80
40 20 0
0
0 0
2
4 6 Time (min)
8
Percent dissolved
Percent dissolved
B
80 60 40 20
4 6 Time (min)
8
75
90
120
240
360
480
Time (min)
10 25 Percent dissolved
100
C
80
60
B 0
2
30 45 Time (min)
80 70 60 50 40 30 20 10 0
0 0
15
10
100
Percent dissolved
A
60
60 40 20
20 15 10 5
C
0 0
0 0
2
4
6
8
10
Time (min)
120
240 Time (min)
360
480
Figure 6 - Dissolution profiles of indomethacin from solid dispersions of indomethacin with (O) PEG 2000, (◊) PEG 6000, (Δ) PEG 20000 and from physical mixtures of indomethacin with: (●) PEG 2000, (◆) PEG 6000, (▲) PEG 20000; compared with (X) pure drug powder and (+) treated pure drug at different pHs: (A) 6.8, (B) 4.6 and (C)1.2 with the ratio of drug:carrier 1:1.
Figure 5 - Dissolution profiles of indomethacin (0 to 10 min) from different formulations: (X) pure drug powder; (+) treated pure drug; physical mixtures with ratios of (●) 1:1, (◆)1:2, (■)1:5, (▲)1:10 and solid dispersions with (O)1:1, (◊)1:2, (❐)1:5, (Δ) 1:10 drug:polymer prepared with (A)PEG 2000, (B) PEG6000 and (C) PEG20000 at pH 6.8.
207
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Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights J. Shokri, J. Hanaee, M. Barzegar-Jalali, R. Changizi, M. Rahbar, A. Nokhodchi
hence, cannot increase the dissolution rate of indomethacin in the medium by an enhanced solubility mechanism.
11.
7. Effects of dissolution media
12.
Comparing the results of dissolution profiles for different PEGs at various pHs show that pH has a substantial effect on the dissolution rate of indomethacin from cogrind formulations. It has already been shown that solid dispersions made with lower molecular weight PEG 2000 produced a faster dissolution rate at pH 6 than those made with higher molecular weight PEG 20000. The results at lower pHs such as pH 4.6 and 1.2 showed that the highest dissolution rate of indomethacin was observed for cogrinds containing the highest molecular weight of PEG (PEG 20000). At these pHs, a direct proportionality between the dissolution rate of indomethacin and molecular weight of PEGs is seen (Figure 6). It seems that the dominant mechanism for controlling the dissolution rate of the drug by PEG at pH 6.8 is the viscosity of the diffusion layer, whereas in the more acidic media (pH 4.6 and 1.2), the solubility enhancement effect of PEG plays the more significant role in the dissolution enhancement of the drug. These results also showed that the acidity of dissolution media could greatly influence the dissolution behaviors of indomethacin in the cogrinds. This could be due to the faster dissolution of PEG 2000 than PEG 6000 and PEG 20000 at higher pH 6.8 [23, 27]. Another reason for the lower dissolution rate of indomethacin from cogrinds containing higher molecular weight of PEGs at pH 6.8 may be due to a reduction in the diffusion coefficient as a result of higher viscosity of the diffusion layer produced by the higher molecular weight PEGs [23].
13.
14.
15.
16. 17.
18.
REFERENCES 1. 2. 3.
4.
5. 6.
7. 8.
9.
10.
19.
KERC J., SRCIC S., KNEZ Z. and SENCAR-BOZIC P.- Micronization of drugs using supercritical carbon dioxide. - Int. J. Pharm., 182, 33-39, 1999 MURA P., FAUCCI T.M. and BETTINETTI G.P.- The influence of polyvinylpyrrolidone on naproxen complexation with hydroxypropyl-β-cyclodextrin. - Eur. J. Pharm. Sci., 13, 187-194, 2001 MURA P., BETTINETTI G.P. and FUCCI T.M. - Interaction of naproxen with crystalline and amorphous methylated beta-cyclodextrin in the liquid and solid state. - Supramol. Chem., 12, 379-389, 2001. BETTINETTI G.P., MURA P., FUCCI M.T, SORRENTI M. and SETTI M. - Interaction of naproxen with noncrystalline acetyl β- and acetyl γ-cyclodextrins in the solid and liquid state. - Eur. J. Pharm. Sci., 15, 21-29, 2002. NYSTROM C. and WESTERBERG M. - Use of ordered mixtures for improving the dissolution rate of low solubility compounds. - J. Pharm. Pharmacol., 38, 161-165, 1986. BARZEGAR-JALALI M., MALEKI N., GARJANI A., KHANDAR A.A., HAJI-HOSSEINLOO M., JABBERI R. and DASMALCHI S. - Enhancement of dissolution rate and anti-inflammatory effects of piroxicam by solvent deposition technique. - Drug Dev. Ind. Pharm., 28, 681-686, 2002. FORD J.L. - The current status of solid dispersions. - Pharm. Acta Helv., 61, 69-88, 1986. VERHEYEN S., BLATON N., KINGEST R. and VAN DEN MOOTER G. - Mechanism of increased dissolution of diazepam from polyethylene glycol 6000 solid dispersions. - Int. J. Pharm., 249, 45-58, 2002. VALIZADEH H., NOKHODCHI A., QARAKHANI N., ZAKERI-MILANI P., AZARMI Sh., HASSAN-ZADEH D. and LOEBENBERG R. - Physicochemical characterization of solid dispersions of indomethacin with PEG 6000, Myrj 52, lactose, sorbitol, dextrin, and Eudragit1 E100. - Drug Dev. Ind. Pharm., 30, 303-317, 2004. NOZAWA Y., MIZUMOTO T. and HIGASHIDE F. - Improving dissolution rates of practically insoluble drug phenytoin by roll mixing with polyvinyl pyrrolidone. - Pharm. Acta Helv., 60, 175177, 1985.
20.
21. 22. 23.
24.
25.
26.
27.
28.
208
CANAL T., LOVERCICH M. and RUBESSA F. - Effect of coprecipitation of phenylbutazone with poly(vinylmethylether/maleic anhydride) on its dissolution behavior. - Pharmazie, 44, 619-621, 1989. FERNANDEZ M., RODRIGUEZ I.C., MARGARIT M.V. and CEREZO A. - Characterization of solid dispersions of piroxicam/polyethylene glycol 4000. - Int. J. Pharm., 84, 197-202, 1992. MURA P., ZEROUK N., MENNINI N., MAESTRELLI F. and CHEMTOB C. - Development and characterization of naproxenchitosan solid systems with improved drug dissolution properties. - Eur. J. Pharm. Sci., 19, 67-75, 2003. SUGIMOTO M., OKAGAKI T., NARISAWA S., KOIDA Y. and NAKAJIMA K. - Improvement of dissolution characteristics and bioavailability of poorly water-soluble drugs by novel cogrinding method using water-soluble polymers. - Int. J. Pharm., 160, 1119, 1998. VAN DER MOOTER G., WUYTS M., BLATON N., BUSSON R., GROBET P., AUGUSTIJNS P. and KINGEST R. - Physical stabilization of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. - Eur. J. Pharm. Sci., 12, 261-269, 2001. ZERROUK N., CHEMTOB C., ARNAUD P., TOSCANI S. and DUGUE J. - In vitro and in vivo evaluation of carbamazepine-PEG 6000 solid dispersions. - Int. J. Pharm., 225, 49-62, 2001. OZEKI T., YUASA H. and KANAYA Y. - Control of medicine release from solid dispersion composed of the poly(ethylene oxide)-carboxyvinylpolymer interpolymer complex by varying molecular weight of poly(ethylene oxide). - J. Controlled Release., 58, 87-95, 1999. OZEKI T., YUASA H. and KANAYA Y. - Controlled release from solid dispersion composed of poly(ethylene oxide)-Carbopol(r) interpolymer complex with various cross-linking degrees of Carbopol(r). - J. Controlled Release., 63, 287-295, 2000. EMAS M. and NYQVIST H. - Methods of studying aging and stabilization of sprayed-congealed solid dispersions with carnuba wax. 1. Micro calorimetric investigation. - Int. J. Pharm., 197, 117-127, 2000. GINES J.M., ARIAS M.J., MOYANO J.R. and SANCHEZ-SOTO P.J. - Thermal investigation of crystallization of polyethylene glycols in solid dispersions containing oxazepam. - Int. J. Pharm., 143, 247-253, 1996. SHIN S.C. and KIM J. - Physicochemical characterization of solid dispersion of furosemide with TPGS. - Int. J. Pharm., 251, 79-84, 2003. TANTISHAIYAKUL V., KAEWNOPPARAT N. and INGKATAWORNWONG S. - Properties of solid dispersions of piroxicam in polyvinylpyrrolidone K30. - Int. J. Pharm., 25, 29-66, 1996. ARIAS M.J., GINES J.M, MOYANO J.R. and RABASCO A.M. - Dissolution properties and in vivo behavior of triamterene in solid dispersions with polyethylene glycols. - Pharm. Acta Helv., 71, 229-235, 1996. OZEKI T., YUASA H. and KANAYA Y. - Application of the solid dispersion method to the controlled release of medicine. IX. Difference in the release of flurbiprofen from solid dispersions with poly(ethylene oxide) and hydroxypropylcellulose and the interaction between medicine and polymer. - Int. J. Pharm., 155, 209-217, 1997. LIN S.Y., CHIEN K.S. and TENG H.H. - Protective colloids and polylactic acid co-affecting the polymorphic crystal forms and crystallinity of indomethacin encapsulated in microspheres. - J. Microencapsulation., 16, 769-776, 1999. OTSUKA M., KATO F. and MATSUDA Y. - Determination of indomethacin polymorphic contents by chemometric near-infrared spectroscopy and conventional X-ray diffractometry. - Analyst, 126, 1578-1582, 2001. SPYCHALA S., BUTKIEWICZ K., PAKULA R. and PICHNEJ L. - Polymorphism of indomethacin: Part II. Identification and rapid determination of polymorphic forms of indomethacin by IR spectroscopy. - J. Pharmacol. Pharm., 29, 157-161, 1977. BETAGERI G.V. and MAKARLA K.R. - Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques. - Int. J. Pharm., 126, 155-160, 1995.
Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights J. Shokri, J. Hanaee, M. Barzegar-Jalali, R. Changizi, M. Rahbar, A. Nokhodchi
29.
30.
31. 32.
33. 34. 35.
TRAPANI G., FRANCO M., LATROFA A., PANTALEO M.R., SANNA E., MACIOCCO E. and LISO G. - Physicochemical characterization and in vivo properties of Zolpidem in solid dispersions with polyethylene glycol 4000 and 6000. - Int. J. Pharm., 184, 121-130, 1999. GUYOT M., FAWAZ F., BILDET J., BONINI F. and LEGUENY A.M. - Physicochemical characterization and dissolution of norfloxacin/cyclodextrin inclusion compounds and solid dispersions. - Int. J. Pharm., 123, 53-63, 1995. ÖZKANY., DOGANAY N., DIKMEN N. and ISIMER A. - Enhanced release of solid dispersions of etodolac in polyethylene glycol. - Farmaco., 55, 433-438, 2000. SEKIKAWA H., NAANUMA T., FUJIWARA, J., NAKANO M. and ARITA T. - Dissolution behaviors and gastrointestinal absorption of phenytoin in phenytoin-PVP coprecipitate. - Chem. Pharm. Bull., 27, 1223-1230, 1979. CRAIG D.Q.M., NEWOTON J.M.- Characterisation of polyethylene glycols using differential Scanning calorimetry.- Int. J. Pharm., 74, 31-41, 1991. SHAH J.C. and CHEN J.R. - Chow D. Preformulation study of etoposide. II. increased solubility and dissolution rate by solidsolid dispersions. - Int. J. Pharm., 113, 103-111, 1995. CHIOU W.L. and RIEGELMAN S. - Preparation and dissolu-
J. DRUG DEL. SCI. TECH., 16 (3) 203-209 2006
36.
37.
tion characteristics of several fast-release solid dispersions of griseofulvin. - J. Pharm. Sci., 58, 1505-1510, 1969. MURA P., FAUCCI T.M., MANDERIOLI G., BRAMANTI P. and PARRINI P. - Thermal behaviour and dissolution properties of naproxen from binary and ternary solid dispersions. - Drug Dev. Ind. Pharm., 25, 257-264, 1999. CORRIGAN O.I. - Retardation of polymeric carrier dissolution by dispersed drugs: factors influencing the dissolution of solid dispersions containing polyethylene glycols. - In: Pharmaceutical Technology: Controlled Drug Release,M.H. Rubinstein Ed., Ellis Horwood Limited, Chichester, 1987, pp. 88-98.
ACKNOWLEGEMENT We would like to thank Dr Taravat Ghafourian for useful discussion and comments.
MANUSCRIPT Received 28 October 2005, accepted for publication 24 March 2006.
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