International Journal of Novel Drug Delivery Technology

Research Article

Solubility enhancement of olmesartan by utilization of solid dispersion and complexation techniques

Tayseer El-nawawy2, Abdel Monaem Swailem2, Dalia Ghorab1*, Samia Nour1
1 2

Department of Pharmaceutics, Faculty of pharmacy Cairo University, kasr El Eni St., Cairo, Egypt. Department of Pharmaceutics, National organization of drug control and research, Dokki, Giza, Egypt.

ABSTRACT
Objective: The aim of the present study was to enhance the dissolution of poorly-water soluble Olmesartan medoxomil by solid dispersion preparation and formation of inclusion complexes. Methods:Solubility determinations prepared by solvent evaporation method and by fusion (melting) method. The inclusion complexes of OLM with BCD were prepared in different D/C ratios (1:1, 1:2, 1:3, 1:4 and 1:5) by kneading method. Results: In comparison to pure drug and the physical mixtures of the different carriers both the drug solubility and its dissolution rate was significantly increased from the different preparations. Particularly, solid dispersions of Drug: Polyethylene glycol 6000 in ratios of 1:3 and 1:5 achieved a rapid and complete drug release within 15 min at pH 6.8. Physical characteristics of Olmesartan medoxomil and solid dispersions prepared were investigated in solid state in terms of morphology by scanning electron microscopy, and characterized by x-ray diffraction, differential scanning colorimetry and Fourier transform infrared spectroscopy. All revealed physical change in the prepared solid dispersion. Such changes were not accompanied by chemical change in any of the polymer or Olmesartan medoxomil. Conclusion : In conclusion, solid dispersion prepared with Polyethylene glycol 6000 by fusion method appeared to alleviate the solubility problems of Olmesartan medoxomil and improved its dissolution profile.

Key Words :Solid dispersion, Polyethylene glycol, Acyclovir.

Received :30 Oct 2012

INTRODUCTION

Accepted:18 Nov 2012

Published: 20 Dec 2012

nhancing the oral bioavailability of poorly soluble drugs by increasing the dissolution rate is one of the most challenging tasks in drug development [1].Therefore, various techniques have been used in attempt to improve solubility and dissolution rates of poorly soluble drugs including solid dispersion (SD), micronization, lipid based formulations, liquisolid compacts and complexation [2]. SD with hydrophilic carriers has been demonstrated as a promising technique for improving the solubility and dissolution rate of poorly-water soluble drugs [3-5]. The improved solubility and dissolution profiles of SD formulation could be explained by the particle size reduction, the change of drug from crystalline to the amorphous form, solubilizing effect of hydrophilic carriers and better wettability of drugs surrounded by carriers [6]. Although spray drying, co-precipitation, co-evaporation and freeze drying techniques are used for SD manufacturing, costly equipments are required along with complicated procedures. However, SD can be simply prepared by fusion (melting) method and solvent evaporation method which usually include two components; the poorly soluble drug and the hydrophilic carrier. PEGs are the most ideal hydrophilic carriers to be used in SD preparation, due to their favorable solution approved by the FDA for internal consumption [7]. Moreover, inclusion complexes as a type of complexation could be used in increasing drug solubility. It is formed by the

insertion of the non polar molecule or the non polar region of one molecule (known as guest) into the cavity of another molecule or group (known as host) [8]. The most commonly used host molecules are cyclodextrins. Hydrophilic cyclodextrins can improve the bioavailability of poorly water soluble drugs in immediate release formulations [9, 10]. Olmesartan medoxomil (OLM) is a non peptide orally active antihypertensive agent acting on the AT1 receptor subtype. Potential advantages of this drug include once-daily dosing, absence of significant adverse reactions, and a well-tolerated side-effect profile. Yet, OLM is poorly soluble and its aqueous solubility is reported to be less than 1mg/ml. The drug is rapidly absorbed following oral administration with a bioavailability of approximately 26%. Peak plasma concentration of OLM occurs 1-2 hours after an oral dose and is highly bound to plasma protein (99%) [11]. Therefore the objective of the present study was to enhance the solubility of poorly soluble OLM through the preparation of SDs by solvent evaporation or fusion methods using PEG 4000, 6000 and 8000 at various drug/carrier ratios, and the preparation of inclusion complex with B-cyclodextrin (BCD). Dissolution profiles in addition to physical characteristics were also investigated in comparison to those of the treated powder. MATERIALS OLM was kindly gifted from Multiapex Company. PEG 4000, 6000 and 8000 were kindly donated from Nile Company. BCD was obtained from Sigma Aldrich. All other chemicals were of reagent grade and all solvents were of HPLC grade. METHODS PHASE-SOLUBILITY STUDIES

Address for correspondence*

Dalia Ghorab Department of Pharmaceutics, Faculty of pharmacy Cairo University, Cairo, Egypt E-mail: dghorb@yahoo.com

e ISSN: 2231-4849
2012 IJNDDT

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Int. J. Novel Drug Deliv. Tech.| Oct-Dec 2012 | Vol-2 | Issue-4 Solubility studies Solubility determinations were performed in triplicate according to the method of Higuchi and Connors [12]. Phase solubility study was performed by adding excess amounts of OLM to solutions of PEG 4000, PEG 6000, PEG 8000 and BCD in ratios (1:1, 1:3, and 1:5) for each in buffer pH 6.8. The mixture of the drug and each carrier was well vortexed and set for stirring using a shaker at room temperature for 48 hours. The samples were filtered using 0.45 m cellulose membrane filter. The solubilised OLM in different solutions was suitably diluted and determined by UV spectrophotometer at max 255nm [13] against blank of pH6.8. Solubility data analysis The value of apparent stability constant, Ks, between drugcarrier combinations were computed from the phasesolubility profiles, as shown in Eqn 1. Ks = Slope/ Intercept (1 - Slope).. (1) Gibbs free energy of transfer (? Gtro) of OLM from pure water to the aqueous solutions of carrier was calculated as in Eqn 2: ? Gtr = -2.303R T Log So/ Ss .. (2) Where So/Ss is the ratio of molar solubility of OLM in aqueous solution of polymer in pH6.8 to that of the same medium without the polymer. Preparation of solid dispersion (SD) SD prepared by solvent evaporation method The drug and each of the carriers ; PEG 4000, PEG 6000 and PEG 8000 were dissolved in 10 ml chloroform in the ratios 1:1, 1:3 and 1:5 w/w for each. The solution of each is then evaporated at room temperature for 24 hours leaving solid residue. The residues were further dried and the solid mass was milled, pulverized, sieved and kept in a dessicator in tightly sealed amber glass colored containers until further analysis SD prepared by fusion (melting) method PEG of various grades 4000, 6000 and 8000 were melted for 5 mins in a porcelain dish on a water bath under stirring, OLM was then added at drug to carrier (D/C) ratios of 1:1, 1:3 and 1:5 (w/w) to the molten carrier. Stirred for 5 min, and allowed to solidify at room temperature. After 24 hours it was milled, pulverized, sieved and stored in dessicator in tightly sealed amber glass colored containers until further analysis. Preparation of inclusion complex The inclusion complexes of OLM with BCD were prepared in different D/C ratios (1:1, 1:2, 1:3, 1:4 and 1:5) by kneading method. Thick slurry was prepared by adding dropwise mixture of 1:1 water: ethanol mixture to the well mixed drug and BCD. Good kneading and stirring took place for 30 min then dried at room temperature for 24 hours. The dried mass was then pulverized sieved and, kept in sealed screw capped amber colored containers till further analysis. Characterization of the prepared SDs Scanning electron microscopy (SEM) The surface morphology of OLM, PEG 6000, OLM /PEG 6000 physical mixture and SD were examined by means of scanning electron microscope (Jeol-JSM-5300 scanning microscope). Electron micrographs of OLM SDs were obtained using a scanning electron microscope operating at 25 kV. The samples were mounted on a glass stub with double-sided adhesive tape and coated under vacuum with gold in an argon atmosphere prior to observation. Micrographs with different magnifications were recorded to study the morphological and surface characteristics of the SD. Fourier transform infrared (FT-IR) spectroscopy FT-IR spectra were obtained using a Perkin Elmer Spectrum RX1 FTIR spectrometer which was employed to characterize the possible interactions between the drug and the carrier in the solid state. Samples of about 2mg were lightly ground and mixed with IR grade dry potassium bromide and then compressed at 10 tones in a hydraulic press for 5min to form discs. The spectra of OLM, PEG 6000, OLM/ PEG 6000 physical mixture and SD were scanned over a frequency range 4000500cm- 1 with a resolution of 4 cm- 1. Differential scanning calorimetry (DSC) DSC thermograms were performed with Perkin-Elmer differential calorimeter to determine the DSC thermal traces. Samples of OLM, PEG6000, their physical mixture or SD were placed in a standard aluminum pan. The instrument was calibrated with indium, dry nitrogen was used as a carrier gas with a flow rate of 30 ml/min and a scan speed of 10?C/min up to 300 ?C was employed. The weight of each sample was 1.5-2 mg. The main transition temperature (TC) was determined as the onset temperature of the highest peak. Enthalpy values were automatically calculated from the area under the main transition peak. Powder X-ray diffraction The powder X-ray diffractometry patterns were traced at room temperature employing an automated Philips PW 1050/25 diffractometer (Philips, Netherlands) for the samples. Monochromatic Cu K_ radiation was obtained with a Ni-filtration and a system of diverging and scattering slits of 1?. The data were collected in step scan mode in the region of 4? = 2_ = 80? with a step size of 0.02? and a dwell time of 0.6 s. About 200mg of each sample powder was carefully side-loaded in a sample holder to minimize possible preferential orientation. In vitro dissolution studies Dissolution studies were assessed in triplets at 37 0.5 oC by the USP Dissolution Tester, Apparatus II (Rotating paddle), using 900 ml of simulated saliva fluid (Sorensen's phosphate buffer, pH 6.8) as the dissolution medium and at a rotation rate of 50 rpm (14). An amount of the SD of the different prepared dispersions equivalent to 20 mg of OLM was introduced into the vessels. At predetermined time points a sample of 5 ml was withdrawn and filtered through 0.45 m membrane filter. The quantity of OLM was determined spectrophotometrically at = 255 nm against blank of pH6.8. Carriers don't absorb UV and did not cause interference at this wavelength. RESULTS AND DISCUSSION Solubility studies In order to optimize the drug: carrier ratio, solubility tests were carried out. The influence of different (D/C) ratio was accurately studied fig. (1) and table (1). The phase-solubility results were in accordance with the well-established formation of soluble complexes between water soluble polymeric carriers and

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Int. J. Novel Drug Deliv. Tech.| Oct-Dec 2012 | Vol-2 | Issue-4 poorly water soluble drugs [15]. There was an increase in the solubility of OLM with the carriers investigated PEG 4000, 6000, 8000 and BCD. The increased solubility may be due to improved dissolution of OLM particles in aqueous solution by water soluble polymers used. An indication of the process of transfer of OLM to the aqueous solutions of water soluble polymers used may be obtained from the values of Gibbs free energy change. Values were all negative for all polymers used at various concentrations indicating the spontaneous nature of drug solubilization. As for the PEG 8000, no increase in solubility was detected by increasing D/C ratio from 1:4 to 1:5. This may be due to the fact that increasing the Mwt of the polymer used from 6000 to 8000 together with increasing the concentration into 1:4 and 1:5 D/C ratio caused crowdness in the medium and hindered the further increase in drug solubility. According to the results recorded in table (1) all the carriers tested enhanced the solubility of OLM. However among the carriers tested PEG 6000 was found to be the best for reaching the maximum solubility at D/C 1:5. Charaterization of the prepared SDs Scanning electron microscopy (SEM) SEM images Fig (2) showed that PEG 6000 particles were irregular in shape and size. OLM PEG physical mixture showed the elongated crystals of the drug over the carrier surface. However, analysis of the SD revealed the absence of these characteristic crystals possibly suggesting the occurrence of physical changes. No separated particles of the drug were observed in the SD. This suggested that the two components were homogenously distributed in the formulation and a solid solution was found which could be responsible for the increase in dissolution rates of OLM which will be discussed lately.

Fig. (1) The effect of different polymers used in various D/C ratios on the phase solubility of OLM. Table (1) Effect of different polymers used in different concentrations and Gibbs free energy on the solubility of OLM.
Polymer Concentration of polymer used (D/C) ratio 1:0 1:1 1:2 1:3 1:4 1:5 1:1 1:2 1:3 1:4 1:5 1:1 1:2 1:3 1:4 1:5 1:1 1:2 1:3 1:4 1:5 Concentration of OLM (mg/ml) at 37C 0.085 0.152 0.160 0.166 0.173 0.180 0.154 0.170 0.206 0.260 0.300 0.250 0.292 0.331 0.382 0.420 0.165 0.213 0.254 0.240 0.240 ? Gtr (J/Mol) ---------- 1498 - 1630 - 1725 - 1832 - 1934 - 1532 - 1787 - 2281 - 2882 - 3251 - 2781 - 3181 - 3504 - 3873 - 4118 - 1756 - 2368 - 2822 - 2676 - 2676
o

Fig.(2) SEM of OLM powder (a), PEG 6000 powder, (b) Physical mixture (c) and SD of OLM with PEG 6000(d). Fourier transform infrared (FT-IR) spectroscopy Further analysis of SD prepared was carried out using IR fig. (3). The infrared spectrum of OLM was characterized by peaks at 1832 and 1706, additionally that of PEG 6000 was characterized by sharp peaks at 3438 and 2886 corresponding to the stretching associated with OH and CH respectively. The IR spectra of SD showed all the principal IR absorption peak of OLM and PEG as they are and similar to the free form proving no chemical interaction between OLM and the carrier used in enhancing its solubility. The decrease in the intensity of the band absorbance could be attributed to the decrease of the amount of the components in the SD prepared. The results obtained from Differential Scanning Colorimetry (DSC) showed that OLM exhibited an endothermic peak at 179 C corresponding to its melting point and an exothermic peak at 230C The carrier used in the SD examined, PEG 6000, showed a melting point at around 63C. Upon dispersing the drug into the polymer used as carrier, the melting endotherm of the free drug disappeared and only the carrier peak was observed. In addition to a little shoulder of the exothermic peak, the absence of the drug melting endotherm in the solid dispersion prepared could be attributed to the complete solubilization and hence distribution of the drug within the hydrophilic matrix of PEG which in turn possibly resulted in the conversion of OLM from the crystalline form to the amorphous form. On the other hand the physical mixture of both the drug and

---------

B-cyclodextrin

PEG4000

PEG 6000

PEG 8000

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Int. J. Novel Drug Deliv. Tech.| Oct-Dec 2012 | Vol-2 | Issue-4 the carrier showed two peaks corresponding to the melting point of both of them.

Fig.(4) DSC thermogram of OLM (a), PEG 6000 (b), their physical mixture (c) and SD formulation (d). Powder X-ray diffraction (PXRD) The powder form of OLM showed various diffraction peaks due to its crystalline structure. The relative reduction of diffraction intensity of OLM at these angles suggests that the size of crystals of drug was reduced. The position of PEG 6000 peak patterns in the physical mixture and solid dispersion were the same and superimposable which again denies the possibility of any chemical interaction and new compound formation between the two components. The solid dispersion showed loss of drug crystallinity due to its melting in the matrix of the used polymer. In optimized solid dispersion, a few less intense and wide diffraction peaks of OLM were detected. This may be due to that the SDs were changed into microcrystalline form and not accompanied by a chemical well defined interaction between the drug and the carrier in any state. Such findings are in agreement with those previously reported by Valizadeh et al [16]. All solid-state characterization of the prepared SDs indicated OLM was present as an amorphous material and entrapped in polymer matrix. In vitro dissolution studies Figures (6-11) and table (2) represent the dissolution profiles of OLM, and the SDs prepared in phosphate buffer (ph

Fig.(3) IR spectrum of OLM (a), PEG 6000 (b), their physical mixture (c) and SD formulation (d).Differential scanning calorimetry (DSC)

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Int. J. Novel Drug Deliv. Tech.| Oct-Dec 2012 | Vol-2 | Issue-4 6.8). In contrast to the very slow dissolution rate of pure OLM (only 12%), the dispersion of the drug in all the polymers used considerably enhanced the dissolution rate. The release of OLM from the SDs prepared using the two different methods were significantly improved when compared to that of the pure drug. The increase in dissolution rate of OLM from SDs of PEG might be due to the reduction of crystal size of the drug, absence of aggregation of drug crystals, its conversion to amorphous or microcrystalline state, and decrease in wettability leading to formation of PEG film surrounding the drug particles and hence decreasing the hydrophobicity of the surface [17] . The dissolution profiles of the formulae prepared using the three grades of PEG showed that by increasing the D/C ratio, the release of OLM increased consequently. These observations indicate the enhanced dissolution of solid dispersion with the increase in carriers' concentration possibly due to increasing the wettability of the drug by carrier, particle size reduction of the drug in the course of the solid dispersion preparation and physical interaction between the drug and carrier. Such observations were in accordance with those previously reported by [17-18].

Fig ( 6) Dissolution profile of OLM from SDs prepared by solvent evaporation using PEG 4000 in D/C ratio 1:1 (S1), 1:3 (S2), 1:5 (S3) and its powder form in pH 6.8.

(a)

(b)

(c)

Fig (7)Dissolution profile of OLM SDs prepared by solvent evaporation using PEG 6000 in D/C ratio 1:1 (S4), 1:3 (S5), 1:5 (S6) and its powder form in pH 6.8.

(d)

Fig. (5) X-ray diffraction pattern of (a) OLM powder (b) PEG 6000 powder (c) OLM -PEG 6000 physical mixture and (d) SD of OLM with PEG 6000 in the same ratio.In vitro dissolution studies The dissolution rates of SD prepared by fusion method were more superior in their dissolution rates than those prepared by solvent evaporation method. This was in agreement with the previously reported results [19]. Formulae prepared by fusion (melting) technique using PEG 6000 showed the fastest drug release. Fusion of olmesartan with PEG 6000 may have resulted in complete dispersion and impregnation of the drug in the carrier. The maximum release was recorded from the formula prepared at the highest D/C ratio 1:5, where 98% of the drug was released after 10 minutes.

Fig (8) Dissolution Profile of OLM from SDs prepared by solvent evaporation using PEG 8000 in D/C ratio 1:1(S7), 1:3 (S8), 1:5 (S9) and its powder form in pH 6.8.

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Int. J. Novel Drug Deliv. Tech.| Oct-Dec 2012 | Vol-2 | Issue-4 Moreover, The formulae prepared by PEG 8000 although it increased the drug release, but to an extent less than those prepared by PEG 6000, by the same method, this may be due to the fact that increasing the molecular weight of the polymer to that extent yielded a bulky and crowded environment which may have restrained the increase in the release rate in case of PEG 8000 than that of PEG 6000. Therefore the carriers tested can be ranked according to their ability in enhancing OLM solubility as follows: PEG 6000 > PEG 8000 > PEG 4000. On the other hand, kneading of OLM with BCD showed an increase in drug release from the inclusion complex formed. Increasing the D/C ratio enhanced the drug release and dispersibility of the drug. The dissolution rate of the drug in inclusion complex overall was evidently higher than that of the pure drug. This can be attributed to increase in drug solubility. The increase in the dissolution of OLM with the increase in BCD could be amorphous form generation of OLM. Inclusion complexes were formed by the insertion of insoluble molecule of OLM into the cavity of the polar BCD. Such theory is supported by wang et al [20]. If the cavity is not large enough the drug is not well accommodated inside it and maximum solubility is not reached. The high solubility of BCD in water resulted in better wettability of drug particles and local enhancement of its solubility at the diffusion layer surrounding the drug particles. The percentage of the dissolved drug from the prepared solid dispersions was higher compared to the physical mixture. The previous explanations were in accordance with those of Rahman et al [21]. The results obtained from the inclusion complexes of OLM with BCD indicated that the stechiometric ratio of OLM with BCD is high (about 1:5) this may be due to the small molecular size of the drug when compared to that of BCD used.

Fig (9) Dissolution profile of OLM from SDs prepared by fusion method using PEG 4000 in D/C ratio 1:1(S10), 1:3 (S11), 1:5 (S12) and its powder form in pH 6.8.

Fig (10) Dissolution profile of OLM from SDs prepared by fusion method using PEG 6000 in D/C in ratio 1:1 (S13), 1:3 (S14), 1:5 (S15) and its powder form in pH 6.8.

Fig (11) Dissolution profile of OLM from SDs prepared by fusion method using PEG 8000 in D/C ratio 1:1 (S16), 1:3 (S17), 1:5 (S18) and its powder form in pH 6.8.

Table (2) Percent released of OLM from the different preparations after 30 minutes phosphate buffer (pH 6.8).
Method of preparation Polymer used D/C Ratio Percent released after 30 mins Method of preparation Polymer used D/C Ratio Percent released after 30 mins Method of preparation D/C Ratio Percent released after 30 mins Solvent evaporation PEG 4000 PEG6000 1:1 1:3 1:5 1:1 1:3 38% 40% 48% 60% 67% Fusion (melting) PEG 4000 PEG6000 1:1 1:3 1:5 1:1 1:3 42% 50% 55% 80% 90% Kneading by B- cyclodextrin 1:1 1:2 1:3 30% 40% 45%

1:5 72%

PEG 8000 1:1 1:3 58% 63% PEG 8000 1:1 1:3 65% 75%

1:5 74%

1:5 98%

1:5 78%

1:4 52%

1:5 60%

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Int. J. Novel Drug Deliv. Tech.| Oct-Dec 2012 | Vol-2 | Issue-4 CONCLUSION From the previous investigations we can conclude that the SDs prepared with the various polymers succeeded in enhancing the OLM solubility. The SD of OLM with PEG 6000 in D/C 1:5 showed the highest solubility enhancement as proved by the phase solubility results together with the highly increased dissolution rate. The fusion (melting) method proved to be superior to the solvent evaporation method in enhancing the solubility. Thus the prepared SD of PEG 6000 prepared by fusion in the ratio of 1:3 and 1:5 could be suggested for further studies by incorporation in fast dissolving tablet preparation of OLM. REFERENCES 1. Planinesk O, Kovacic B and Vercer F. Carvedilol dissolution improvement by preparation of solid dispersion with porous silica. Int. J. pharm. 2011; 406 (1-2): 41-48. Saharan V, Kukkar V, Kataria M, Gera M and Choudhury P. Dissolution enhancement of drugs. Part I: technologies and effect of carriers. Int. J. Health Res. 2009; 2:107124. Vasconcelos T, Sarmento B and Costa P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discovery Today 2007; 12: 10681075. Sinha S, Ali M, Baboota S, Ahuja A, Kumar A and Ali J. Solid dispersion as an approach for bioavailability enhancement of poorly water-soluble drug ritonavir. AAPS Pharm. Sci. Tech. 2010; 11: 518527. Han H, Lee B and Lee H. Enhanced dissolution and bioavailability of biochanin A via the preparation of solid dispersion: In vitro and in vivo evaluation. Int. J. Pharm. 2011; 415: 89-94. Ahuja N, Katare O P and Singh B. Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers. Eur. J. Pharm. Biopharm. 2007; 65: 2638. Szuts A, Lng P, Ambrus R, Kiss L and Deli MA. Applicability of sucrose laurate as surfactant in solid dispersions prepared by melt technology. Int. J. Pharm. 2011; 410: 107110. Bindu M, Kusum B and Banji D. Novel strategies for poorly water soluble drugs. Int. J. Pharm.l Sci. Rev. and Res. 2010; 4(3) Article 14. Ahuja A, Challa R, Khar R and Ali J. Cyclodextrins in Drug Delivery: An Updated Review. AAPS Pharm. Sci. Tech. 2005; 6: 2-8. Development of meloxicam formulations utilizing ternary complexation for solubility enhancement. Pakist J Pharm Sci 2011; 24 (4): 533-538. 11. Daryl N, Evans B III, Bridget S and Marlon H. Olmesartan Medoxomil for Hypertension: A Clinical Review. Drug forecast 2002; 27(12): 611-18. 12. Higuchi T and Connors K. Phase solubility techniques. Advanc. Anal. Chem. Instrument. 1965; 4: 17 123. 13. Ambadas R, Rote and Pankaj D. Bari, Ratio Spectra Derivative and Zero-Crossing Difference Spectrophotometric Determination of Olmesartan Medoxomil and Hydrochlorothiazide in Combined Pharmaceutical Dosage Form, AAPS Pharm. Sci. Tech. 2009 Dec.; 10(4): 12001205.. 14. Frick A, Moller H and Wirbitzki E. biopharmaceutical characterization release drug products. Comparison pencillin potassium, glimepride and Pharm. Biopharm 1998; 46:305. In vitro and in vivo of oral immediate of phenoxy methyl levofloxacin. Eur. J.

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