Solubility Enhancement of Poorly Water Soluble Drug by Solid Dispersion Technique
Ahmed Samir1, Nagia El-Megrab1, Hanaa A. Fattah1, Waleed Barakat2
Departments of 1Pharmaceutics, 2Pharmacology, Faculty of Pharmacy, Zagazig University, Egypt.
*Corresponding Author E-mail: dr_scheva99@yahoo.com
ABSTRACT:
The objective of present was to improve the solubility of Clonazepam (CZP), poorly water soluble drug, by solid dispersion technique using Polyethylene glycol 6000 (PEG 6000) and Urea (UR) as carriers. The Solid dispersion was prepared by physical mixing and solvent evaporation method. The interaction of the Clonazepam with PEG 6000 and UR was evaluated by the Fourier transform infrared (FTIR) spectroscopy; Differential scanning Calorimetry (DSC) and X-ray diffraction patterns (XRD). The results from the FTIR and XRD analyses showed that Solid dispersion might exist in the amorphous form. A DSC result showed that the sharp melting point was completely disappeared suggesting that the CZP molecularly dispersed in an amorphous form. Dissolution studies indicate that dissolution rate was remarkably increased in Solid dispersion as compared to the physical mixture and drug alone. Also the pharmacological studies of the selected formulations [(1:3 CZP : PEG 6000) and (1:2 CZP : Urea)] were performed. In conclusion PEG 6000 and UR can be a well utilized to increase the solubility of poorly water soluble drugs.
KEY WORDS: Clonazepam, solid dispersion, Polyethylene glycol 6000, Urea.
Status epileptics is a neurological disorder, which requires quick management of seizures in order to avoid the risk of permanent brain damage.
Clonazepam, a benzodiazepine derivative is used widely in the treatment of status epileptics. Clonazepam is preferred over other benzodiazepines due to its longer duration of action (24 h). Clonazepam, the drug of choice in suppression of myoclonic seizures, acts by increasing the effectiveness of the inhibitory neurotransmittor, gamma amino butyric acid, within the central nervous system (Rey et al., 1999).
In 1971 Chiou and Riegelman defined solid dispersion as “A dispersion of one or more active ingredient in an inert carrier or matrix at solid state prepared by melting (fusion), solvent evaporation or melt, solvent method”. Solid dispersion when exposed to aqueous media, the carrier is dissolved; the drug is released as very fine colloidal particles (Chiou and Reigelman, 1971) and widely used to increase intrinsic solubility or dissolution and further the bioavailability of drug (Serajuddin, 1999; Chiou and Riegelmann 1969). Various carriers can be used for solid dispersion preparation which includes polyethylene glycol, poly vinyl pyrolidone, urea, mannitol, poloxamers etc. Solid dispersion can be prepared by conventional methods such as solvent evaporation method, fusion method and melt solvent method and novel methods used for preparation includes super critical fluid technology, electrospining, spray drying, lyophilization and melt extrusion method (Sharma and Joshi, 2007).
Pentylenetetrazole (PTZ) is a convulsant used to model epileptic seizures in animals (Cremer et al., 2009 and Bertram, 2007).
The aim of the present study was to characterize the solid state properties of the solid dispersion system of clonazepam in PEG 6000 and Urea prepared at different ratios. The methods of characterization were achieved through using different tools as differential scanning calorimetry (DSC), powder X-ray diffractory (XRD) and Fourier transform infrared (FTIR). Also, solubility and dissolution rate study were performed to qualify the solid dispersion in comparison to the drug alone or as a physical mixture (PM). Moreover, the formulations of CZP which showed the highest dissolution rate and release were selected to study the anticonvulsant activity.
2. EXPERIMENTAL:
2.1. Materials:
Clonazepam (kindly supplied by EIPICO Co. Egypt), Methanol, Ethanol, (PEG) 6000 and UR (Kindly supplied by El.Gomhouria Co., Egypt)
Pentylenetetrazole (SIGMA ALDRISH, China) and Commercial product of Clonazepam (Amotril®) (AMOUN Pharmaceutical Co., Cairo, Egypt). All other materials and reagents were of analytical grade.
2.2. Methods
2.2.1. Preparation of physical mixture
Physical mixtures were prepared by triturating appropriate quantities of CZP and carriers using a mortar and pestle, at 1:1, 1:2, 1:3 and 1:6 weight ratio of CZP: carrier then transferred to a vaccum desiccator until ready for use. Powder of PMs were sieved to obtain particles passing through 355 μm and retained on 150 μm sieve.
2.2.2. Preparation of solid dispersions
Clonazepam and different carriers PEG 6000 and urea were weighed accurately in various ratios (1:1, 1:2, 1:3, 1:4, 1:5 and 1:6) and dissolved in sufficient quantity of ethanol which was stirred at room temperature, and the solvent was then removed under vacuum at a maximum temperature of 40oC. Solid residue was dried in a vacuum oven for 24 h at room temperature, pulverized and sieved. Powdered samples below 420 um (40 mesh) were stored in closed containers away from light and humidity until use. (Vadnere, 2002).
2.2.3. Fourier transform infrared spectroscopy (FTIR):
FTIR spectroscopy was employed to characterize the possible interactions between the drug and the carrier in the solid state on a FTIR spectrophotometer using KBr disk method. The scanning range was 200-4000cm-1 and the resolution was 1 cm-1.
2.2.4. Differential Scanning Calorimetry (DSC):
The possibility of any interaction between the drug and the carriers during preparation of physical mixture and solid dispersion was assessed by carrying out thermal analysis of drug and polymer alone as well as physical mixture and solid dispersion using DSC. The DSC thermograms were recorded on a Shimadzu-Dsc 50. Samples (1.5 mg) were heated in hermetically sealed aluminum pans over the temperature of 30-300 ºC at a constant rate of 10 ºC /min under a nitrogen purge (30 ml/min).
2.2.5. X-ray diffraction (XRD):
To determine powder characteristics, X-ray powder diffraction studies of drug and polymer alone as well as physical mixture and solid dispersion was performed. X-ray diffraction patterns were obtained using a Siemens Kristallofex D-5000 powder diffractometer with CuKα radiation. Diffractograms were run at a scanning speed of 8º/ min over the 2θ range of 0-80º.
2.2.6. Solubility measurements:
An excess amount of CZP was placed into a 25-ml glass vial containing various concentrations of each carrier in 10 ml water. The glass vials were closed with stopper. The content of the suspension was equilibrated by shaking in a thermostatically controlled water bath at 25 ºC for all the carriers for 24 hrs. After attainment of equilibrium, the content of each vial was then filtered through a double layered filter paper (Whatman 42). The filtrate was suitably diluted and assayed spectrophotometrically at λmax 309 nm to measure the amount of dissolved drug. All experiments were conducted in duplicate.
2.2.7. Release rate studies:
The dissolution of CZP from pure drug, the prepared (SDs) and (PMs) was carried out according to the USP-24, rotating paddle method. Dissolution medium consisting of 250 ml of distilled water was used. The stirring rate was 100 rpm and the temperature was maintained at 37+ 0.5 ºC. A sample of 2 mg of CZP or its equivalent of the (SDs) or the (PMs) was placed on the surface of the dissolution medium. At appropriate time intervals (5, 10, 20, 30, 60, 120 min), 5 ml samples were withdrawn and replaced with an equivalent amount of the fresh dissolution medium kept at 37 ºC. The samples were filtered rapidly through a double layered filter paper (Whatman 42), diluted with dissolution medium and assayed spectrophotometrically at λmax 309 nm without the interference from the carriers. All experiments were conducted in duplicate.
2.2.8. Pharmacological study:
All experiments were performed on adult male Swiss mice weighing 22-26 g. The animals were randomly assigned to experimental groups comprising 8 mice per group. All animal experiments were approved by the ECAHZU (Ethical Committee for Animal Handling at Zagazig University).
Clonic convulsions were induced in mice by s.c. administration of PTZ (98mg/kg). Following PTZ administration, mice were placed separately into cages (24 cm x 15 cm x 10 cm) and observed for 30 min for the occurrence of clonic seizures. Clonic seizure activity was defined as clonus of whole body lasting over 3 s, with an accompanying loss of righting reflex.
The number of animals convulsing out of the total number of the mice tested was noted for control animals. A group of mice (28 mice) were injected with PTZ s.c. at a dose of 98 mg/kg, then the total number of the mice convulsing out from the total animals tested was noted and taken as the control group. The anticonvulsant activity of CZP formulations against the clonic phase of PTZ-induced seizures was determined after s.c. administration of PTZ.
Figure (1): XRD diffractograms for: a) (CZP) clonazepam; b) (PEG) polyethylene glycol 6000, and their different systems prepared at different ratios; c) (PM) physical mixture; d) (SD) solid dispersion.
Figure (2): XRD diffractograms for: a) (CZP) clonazepam; b) Urea, and their different systems prepared at different ratios; c) (PM) physical mixture; d) (SD) solid dispersion.
Figure (3): DSC thermograms for; a) (CZP) clonazepam; b) (PEG) polyethylene glycol 6000, and their different systems prepared at different ratios; C) (PM) physical mixture; d) (SD) solid dispersion.
Figure (4): DSC thermograms for; a) (CZP) clonazepam; b) urea, and their different systems prepared at different ratios; c) (PM) physical mixture; d) (SD) solid dispersion.
All formulations were administered orally in a volume 0.008 ml/g body weight. The selected formulations were orally administered 30 min before PTZ administration. PTZ administered subcutaneously (s.c.) into a loose fold of skin in the midline of the neck in a volume 0.005 ml/g body weight.
3. RESULTS AND DISCUSSION:
3.1. X-ray powder diffraction (XRD)
XRD patterns for different samples are displayed in fig.1 and 2 for CZP-PEG 6000 and CZP-UR systems, respectively. CZP was a highly crystalline powder with characteristic diffraction peaks at 2θ of 11.79o, 22.84o, 23.05o and 23.75o, in addition there were some other peaks of lower intensity.
In case of untreated PEG 6000 (fig. 1), there were sharp peaks at 19.23o, 23.14o and 23.45o, while in case of PEG 4000 (SD), the diffraction peaks were traced at 19.15o and 23.28o. The diffraction pattern of PEG 6000 solid dispersions and physical mixtures are nearly identical to that of untreated ones. The peaks of CZP were missing, thus indicating that CZP was in amorphous form. This was in line with our findings from DSC and FTIR analysis where interactions might be present between the drug and either of these two carriers. While Urea in pure form revealed high degree of crystallinity and the diffraction peak was traced at 22.37o. In case of urea solid dispersions and physical mixtures, the diffraction peaks of CZP were not observed whereas the diffraction peaks of urea were noted (fig.2). This indicated that CZP was in amorphous state (Okonogi et al., 1997). No new peaks could be observed suggesting the absence of the chemical interaction between the drug and the carrier (Ahuja et al., 2007).
3.2. Differential scanning calorimetry (DSC)
Fig. 3 depicted thermograms of CZP, PEG 6000, their PMs and SDs. DSC curves of pure CZP exhibited a sharp endothermic peak at 235.35oC (table 1), which is corresponding to its melting point.
Mura et al., 1999, studied the DSC scans of SD of naproxen in binary systems with different PEG molecular weights, they observed the disappearance of the drug melting peak which indicated the dissolution of the naproxen in the melted carrier. A slight change occurs in the shape of PEGs endothermic peaks which appeared broadened in solid dispersions.
The DSC thermograms of CZP-PEG 6000 solid dispersions and corresponding physical mixtures showed no CZP endothermic peak but did exhibit the endothermic peaks due to the fusion of the carriers. This result indicated that CZP might be in amorphous state. Fig. 4 illustrates the DSC thermograms of CZP -urea systems and the absence of CZP peak and the predominance of urea peaks. This suggests that CZP is completely soluble in liquid phase of urea (Domain et al., 2000).
Table (1): Fusion temperature and Heat of Fusion (ΔHF) of some CZP solid dispersions and physical mixtures compared with individual components.
|
System |
Fusion temperature (oC) |
Heat of fusion (ΔHF) (J/g) |
|
CZP |
235.35 |
106.72 |
|
PEG 6000 |
63.01 |
183.06 |
|
CZP -PEG 6000 (PM) (1:3) |
62.42 |
118.88 |
|
CZP -PEG 6000 (SD) (1:3) |
62.65 |
146.09 |
|
UR |
134.79 |
210.28 |
|
CZP – UR (PM) (1:2) |
134.35 |
128.88 |
|
CZP – UR (SD) (1:2) |
132.77 |
116.12 |
3.3. Fourier Transform Infrared spectroscopy (FTIR):
The FTIR of CZP, PEG 4000, Urea (PMs and, SDs) as shown in fig 5, 6 respectively. In spectra of CZP with UR (fig. 5), no differences in the position of the absorption bands was observed, hence providing evidence for the absence of any chemical interactions in the solid state between CZP and these carriers. In the PM and SD spectra, C=O and N-H of UR were overlapped with C=O and N-H of CZP, which formed two broad bands around 3448.5 cm-1(Silverstein et al., 1991).
In case of PEG 4000 (fig. 6), the carbonyl stretching band of CZP that appeared at 1693.4 cm-1 decreased in intensity with the disappearance of C-H stretching band and N-H stretching band and predominance of O-H band corresponding to PEGs. It was concluded from the chemical structures that an interaction of a significant magnitude could be present between the aromatic hydrogen of the drug and the hydroxyl groups of PEG. Mukne and Nagarsenker, 2004 attributed the complete disappearance of the aromatic stretching vibrations of the phenyl group of triameterene by its complexation with ß-cyclodextrin to be due to the significant interaction between the phenyl group of triametrene and the cyclodextrin.
3.4. Solubility
determination:
The aqueous solubility of a drug is a prime determinant of its dissolution rate and compounds with aqueous solubility less than 0.1 mg/ml often present dissolution limitation to absorption. The solubility of CZP in distilled water at 25oC was found to be 0.0012 + 0.007 mg/ml (Hammad and Müller, 1998).
Figure (7) depicted the effect of different carriers on CZP solubility in distilled water at 25ºC. In case of PEG 6000 and urea, the solubility of CZP linearly increased as the carrier concentration increased, showing the feature of an AL-type solubility phase diagram (Higuchi and Connor, 1965). This result illustrates that the complex formed was soluble and did not form precipitate over the range of the carrier concentration.
On the other hand, the solubility plot of Urea showed a Bs-type curve (Higuchi and Conners, 1965). The initial rising portion was followed by a decrease in total concentration of CZP. Consequently, these carriers can be ranked according to its effect on increasing the solubility of CZP as PEG 6000 > urea. The increased solubility of CZP in carrier’s solution may be attributed to both complex formation and reduction in interfacial tension of water and hence intermolecular forces and polarity caused by the presence of those carriers (Al-Angary et al., 1996).
Figure (7): Phase solubility diagram of CZP in water at 25ºC in presence of PEG 6000 and urea
Figure (5): FTIR spectra for; a) (CZP) clonazepam; b) Urea, and their different systems prepared at different ratios; c) (PM) physical mixture; d) (SD) solid dispersion.
Figure (6): FTIR spectra for; a) (CZP) clonazepam; b) (PEG) polyethylene glycol 6000, and their different systems prepared at different ratios; c) (PM) physical mixture; d) (SD) solid dispersion.
3.5. Release rate studies:
The dissolution profiles of pure CZP, its PMs and SDs with different carriers are shown in (Figs. 8 and 9). Data are average of three measurements.
The calculated dissolution parameters revealed that, pure CZP yielded the slowest dissolution rate with only about 9.09% of the drug dissolved in 120 min. The hydrophobic property of CZP prevented its contact with the dissolution medium (distilled water) which led to a slow dissolution rate (Tantishaiyakul et al., 1996). As shown in tables 2 and 3, all PMs released the CZP at faster rate than the drug alone as reflected by higher initial dissolution rate (IDR) and greater extent of dissolution after 120 min. These results can be explained on the basis that dry mixing brings the drug in close contact with the hydrophilic polymer (Van den Mooter et al., 1998). Also this may be due to a possible solubilization effect by the carrier operating the microenvironment (diffusion layer) that immediately surrounds the drug particles in the early stages of solubilization (Arias et al., 1996).
During dissolution experiments, it is apparent that, the rate and the extent of dissolution of CZP from (SDs) exceeded those of pure CZP or the corresponding (PMs). The dissolution efficiency (DE%) of (1:3) CZP- PEG 6000 co-precipitate (table 2) was 31.45 %, while the DE% of the corresponding physical mixture was only 17.17%. In case of urea, the DE% of (1:2) CZP-urea co-precipitate (table 3) was 26.43 %, while for its PM was 19.13 %. The observed higher dissolution of the prepared (SDs) could possibly be due to the solubilizing effect of the carriers that may operate in the diffusion layer immediately surrounding the drug particles. Also, each single crystallite of the drug was very intimately encircled by the soluble carrier particles which can readily dissolve and cause the aqueous medium to contact and wet the drug particles easily (Etman, 2000). Moreover, it can be generally assumed that the increased dissolution via (SDs) could be explained on the basis of alterations in the solid-state structures of the carriers and the drug particles. These structural changes include the formation of solid solution, eutectic mixtures or soluble complex between the drug and the carriers and formation of amorphous drug particles or loss of crystallinity of the drug. For most (SDs), more than one of these factors may probably be responsible for the dissolution enhancement (Trapani et al., 1999 and Mura et al., 1999).
Table (2): Dissolution parameters (±SD) of clonazepam in distilled water from different clonazepam-PEG 6000 systems.
|
Composition (w/w) |
IDR (% dissolved /min) |
PD20 (%) |
PD60 (%) |
DE*100 (%) |
|
Clonazepam Powder |
0.21+0.08 |
4.19+1.68 |
7.27+0.33 |
4.66+1.13 |
|
Clonazepam-to- PEG 6000 |
|
|
|
|
|
PM 1:1 SD 1:1 |
0.68+0.02 1.25+0.03 |
13.71+0.47 25.08+0.73 |
17.62+0.72 36.34+0.45 |
9.31+1.31 27.40+ 0.51 |
|
PM 1:2 SD 1:2 |
0.86+0.08 1.21+0.05 |
17.13+1.60 24.24+1.01 |
26.04+2.35 34.04+1.33 |
13.65+ 2.34 26.78+ 1.09 |
|
PM 1:3 SD 1:3 |
1.11+0.04 1.50+0.03 |
22.18+0.85 29.93+0.61 |
30.97+1.53 38.69+2.38 |
17.17+1.39 31.45+ 1.47 |
|
PM 1:4 SD 1:4 |
0.84+0.02 0.72+0.07 |
16.74+0.48 18.34+1.54 |
23.55+0.97 28.54+0.08 |
14.22+ 1.38 20.79+1.40 |
|
PM 1:5 SD 1:5 |
0.79+ 0.03 0.81+ 0.02 |
15.91+0.70 16.22+0.46 |
22.21+0.98 26.26+0.28 |
13.54+0.40 15.58+ 0.28 |
|
PM 1:6 SD 1:6 |
0.76+ 0.02 0.82+ 0.01 |
15.31+0.44 16.53+0.24 |
20.36+1.73 24.53+0.44 |
13.16+0.43 18.78+0.28 |
IDR = Initial dissolution rate. PD20 = Extent of dissolution after 20 min
PD60 = Extent of dissolution after 60 min DE% = Dissolution efficiency after 60 min
Figure (8): Dissolution profile for CZP-PEG 6000 systems in pure distilled water prepared at different ratios of CZP:PEG 6000.(CZP) clonazepam; (PM) physical mixture; (SD) solid dispersion.
3.6. Pharmacological studies:
3.6.1. Threshold for PTZ-induced clonic seizures
PTZ at a dose of 98 mg/kg induced clonic seizure in 85.7% of mice (24 out of 28 mice injected).
3.6.2. Anticonvulsant effect of CZP formulations:
CZP formulations (CZP-PEG 6000 1:3 and CZP-urea 1:2) were administered orally at dose of 0.02 mg/kg (Jastrzebska et al., 2009) 30 min before the convulsive dose of PTZ and the animals were monitored for 30 min and the number of the convulsive animals was recorded in each group (table 4).
In group 1 (vehicle treated group), all animals showed clonic seizures lasting for over 3 s with loss of righting reflex at a time ranging from 5-7 min which was taken as the end point.
In group 2 (receiving CZP-PEG 6000), all animals were protected against clonic convulsion.
In group 3 (receiving CZP-urea), two animals showed the convulsion at 3.38 min and 11.51 min.
In group 4 (receiving CZP- commercial product (Amotril®), seven animals showed clonic convulsions at 3.01, 3.50, 4.52, 5.20, 5.58, 11.30 and 15.37 min.
Table (3): Dissolution parameters (±SD) of clonazepam in distilled water from different clonazepam-PVP systems.
|
Composition (w/w) |
IDR (% dissolved /min) |
PD20 (%) |
PD60 (%) |
DE*100 (%) |
|
Clonazepam Powder |
0.21±0.08 |
4.19+1.68 |
7.27+0.33 |
4.66+1.13 |
|
Clonazepam-to- UR |
|
|
|
|
|
PM 1:1 SD 1:1 |
0.73+0.16 0.95+0.01 |
14.52+3.23 22.71+0.67 |
25.03+2.39 29.35+3.78 |
17.26+2.05 21.67+1.15 |
|
PM 1:2 SD 1:2 |
0.74+0.08 1.24+0.07 |
14.94+1.70 24.80+1.44 |
27.80+1.70 34.15+0.45 |
19.13+1.75 26.43+0.26 |
|
PM 1:3 SD 1:3 |
0.69+0.01 0.99+0.04 |
13.85+0.22 19.78+0.99 |
19.53+2.05 27.57+1.77 |
15.35+1.19 21.12+0.93 |
|
PM 1:4 SD 1:4 |
0.66+0.01 0.98+0.01 |
13.17+0.28 19.65+0.29 |
21.47+2.85 28.65+3.20 |
13.02+1.67 21.15+0.68 |
|
PM 1:5 SD 1:5 |
0.71+0.02 1.087+0.13 |
14.32+0.43 21.75+2.73 |
21.13+0.88 27.44+0.57 |
15.93+1.24 21.06+0.73 |
|
PM 1:6 SD 1:6 |
0.63+0.04 0.99+0.01 |
12.60+0.81 19.89+0.37 |
18.87+0.92 29.29+1.54 |
13.02+0.49 21.15+0.32 |
IDR = Initial dissolution rate. PD20 = Extent of dissolution after 20 min
PD60 = extent o dissolution after 60 min DE% = Dissolution efficiency after 60 min
Figure (9): Dissolution profile for CZP-urea systems in pure distilled water prepared at different ratios of CZP: urea.(CZP) clonazepam; (PM) physical mixture; (SD) solid dispersion
Table (4): Anticonvulsant effect of CZP formulations against PTZ induced clonic seizures.
|
Group No. |
Treatment (mg/kg) |
Number of animals protected /group |
(% of animals protected) |
|
1 |
Distilled water |
0/8 |
0 |
|
2 |
(1:3) CZP-PEG 6000 |
8/8 |
100 % |
|
3 |
(1:2) CZP-urea |
6/8 |
75 % |
|
4 |
Commercial formulae (Amotryl®) |
1/8 |
12.5% |
These results demonstrated that Clonazepam formulations show better and more efficient pharmacological effect than commercial formulae against PTZ-induced seizures. This may be attributed to the enhanced dissolution of the drug from SDs (Arias et al., 1996).
4. CONCLUSION:
The study has demonstrated that dispersion of CZP into water-soluble carriers like PEG 6000 or urea changed the crystallinity of CZP according to type and amount of the polymer. The formation of CZP-PEG 6000 or CZP-urea represents a suitable modification for improving its availability. Many factors contributed to faster release rate such as a decrease in particle size, a decrease in agglomeration of particles, an increase in wetability and a decrease in crystallinity of the drug.
Pharmacological results have proven that Clonazepam formulations show faster, better and more efficient pharmacological effects than commercial formulae against PTZ-induced seizures.
5. REFERENCES:
1. Vadnere, M. K., Coprecipitates and Melts. In: Swarbrick J Boylan J Eds Encylopedia of Pharmaceutical Technology. 2nd ed. NY, Marcel Dekker Inc. 641, 643 (2002).
2. Sharma, D. K., and Joshi, S. B., Solubility enhancement strategies for poorly water-soluble drugs in solid dispersions: A Review. Asian J. Pharmaceutics., 1 (1):9, 19 (2007).
3. Chiou, W. L., and Reigelman, S., Preparation and dissolution characteristics of several fast release solid dispersion of griseofluvin. J. Pharm. Sci., 58: 1505, 1059 (1969).
4. Serajuddin, T. M., Solid dispersion of poorly water soluble drugs: early promises, subsequent problems and recent breakthrough. J. Pharm. Sci., 88 (10): 1058, 1066 (1999).
5. Chiou, W. L., and Reigelman, S., Pharmaceutical applications of solid dispersions. J. Pharm. Sci., 60: 1281, 302 (1971).
6. Rey, E., Treluer, J. M., and Pons, G., Pharmacokinetic optimization of benzodiazepine therapy for acute seizures. Focus on delivery routes. Clin. Pharmacokinet., 36:409, 424 (1999).
7. Ahuja, N., Katare, O. P. and Singh, B., Studies on dissolution enhancement and mathematical modelling of drug release of a poorly water-soluble drug using water soluble carriers. Eur. J. Pharm. Biopharm. 65, 26–38 (2007).
8. Al-Angary, A. A., Al-Meshal M. A., Bayumi, M. A. and Khidr, S. H., Evaluation of Liposomal Formulations Containing the Anti-malarial Agent or Tether, Int. J. Pharm., 128, 163‑168 (1996).
10. Bandi, N., Wei, W., Roberts, C.B., Kotra, L.P. and Kompella, U.B., Preparation of budesonide and indomethacin–hydroxy-propylbeta- cyclodextrin (HPBCD) complexes using a single-step, organic-solvent-free supercritical fluid process. Eur. J. Pharm. Sci. 23, 159–168 (2004).
11. Bertram, E., The relevance of kindling for human epilepsy, Epilepsia, 48 (Suppl 2),65–74, (2007).
12. Bogdanova, S., Bontcheva, E. and Avramova, N., Phase characterization of indomethacin in adsorbates onto hydroxyl-ethylcellulose. Drug Dev. Ind. Pharm. 33, 900–906(2007).
15. Etman, A. M., Praziquantel Solid Dispersions with Polyethylene Glycol and Urea: Preparation, Characterization and In Vitro Dissolution, Alex .J. Pharm. Sci., 14 (1), 79 (2000).
16. Etman, M.A. and Nada, A.H., Hydrotropic and cosolvent solubilisation of indomethacin. Acta Pharm. 49, 291–298 (1999).
17. Hammad, M. A. and Müller, B. W., Solubility and stability of clonazepam in mixed micelles, Int. J. Pharm., 169, 55–64 (1998).
18. Higuchi, T. and Connors, K.A., Phase solubility techniques, Adv. Anal. Chem. Instrum., 4, 117-210 (1965).
19. Hirasawa, N., Ishise, S., Miyata and H., Danjo, K., Physicochemical characterization and drug release studies of nilvadipine solid dispersions using water-insoluble polymer as a carrier. Drug Dev. Ind. Pharm. 29, 339-344 (2003).
20. Jastrzebska M. D., Andres-Mach M. M., Ratnaraj N., Patsalos P. N., Czuczwar S. J. and Luszczki J. J., Isobolographic characterization of the anticonvulsant interaction profiles of levetiracetam in combination with clonazepam, ethosuximide, Phenobarbital and valproate in the mouse pentylenetetrazole-induced seizure model, Seizure, 18, 607–614 (2009).
21. Krasowska, H., Effect of micellar solubilization on the gastrointestinal absorption of indomethacin in the rate. Int. J. Pharm. 7, 137–143 (1980).
23. Mura, P., Faucci, M.T., Manderioli, A., Bramanti, G. and Parrini, P., Thermal behavior and dissolution properties of naproxen from binary and ternary solid dispersions, Drug Dev. Ind. Pharm., 25 (3), 257-264 (1999).
24. Okonogi, S., Ogushi, T., Yonemochi, E., Puttipiatkhachorn, S. and Yamamoto, K., Improved dissolution of ofloxacin via solid dispersion, Int. J. Pharm., 156, 175 (1997).
25. Tantishaiyakul, V., Kaewnopparat, N. and Ingkatawornwong, S., Properties of solid dispersions of piroxicam in polyvinylpyrrolidone K-30., Int. J. Pharm., 143, 59 (1996).
27. Valizadeh, H., Nokhodchi, A., Qarakhani, N., Zakeri-Milani, P., Azarmi, S., Hassanzadeh, D.L. and Lo¨ benberg, R., Physicochemical characterization of solid dispersions of indomethacin with PEG 6000, Myrj 52, lactose, sorbitol, dextrin, and Eudragit E100. Drug Dev. Ind. Pharm. 30, 303–317 (2004).
28. Van den Mooter, G., Augustijns, P., Blaton, N. and Kinget, R, Physico-chemical characterization of solid dispersions of temazepam with polyethylene glycol 6000 and PVP K30, Int. J. Pharm., 164, 67-80 (1998).
Received on 06.02.2012 Modified on 13.02.2012
Accepted on 18.03.2012 © AJRC All right reserved
Asian J. Research Chem. 5(4): April 2012; Page 483-491