Neeti NEMA, Nimesh SINGH, Archna PANDEY
Dr. Hari Singh Gour University, INDIA
Abstract. The purpose of present study is to investigate the effect of Polyethyl- ene glycol (PEG) upon the solubility of antifungal drug Ketoconazole (KTCZ). KTCZis water insoluble drug. For water insoluble drugs difficulties are usually encounteredin selecting dissolution medium with a good discriminating power. In the present study,a dissolution medium based on solubility data is developed for KTCZ. The solubility ofKTCZ in various fluids such as purified water (pH 6.4), cetyl trimethyl ammoniumbromide (CTAB), sodium lauryl sulphate (SLS), Polyethylene glycol (PEG) and alsoin 0.1 M sulphuric acid containing SLS, CTAB, PEG (at their critical micellar concen-trations (CMC) values) was determined. The solubility of KTCZ is increased by 2.51fold in PEG + purified water system. The surprising increase in solubility of same drugby 7.29 fold is found in PEG + 0.1 M H SO system. Polymeric surfactants (PEG 400) form nanoscopic core-shell structures above the critical micellar concentrations.
The hydrophobic drugs while the hydrophobic part serve as reservoirs for hydropho-bic drugs while the hydrophilic part serves as interface between the bulk aqueousphase and the hydrophobic domain. This unique architecture enables polymeric mi-celles to serve as nanoscopic depots or stabilizers for poorly water-soluble compounds.
A new spectrophotometric method was also proposed for the determination of KTCZin pure form and pharmaceutical formulation. This method is based on the redox-complexation reactions, which proceed in the ketoconazole, ammonium metavanadateand PEG system and form a red-brown colored complex with absorption maxima ofV(V) at 375 nm. A linear calibration graph was obtained between 1.06 µg/mL – 21.25µ g/mL of KTCZ. The results of analysis have been validated statistically and by re-covery studies. The proposed method is simple, rapid, sensitive and economic.
Keywords: spectrophotometry, ketoconazole, formulations, validation, solubility, Introduction
1ylmethyl)-1,3-dioxolon-4-yl]methoxy piperazin (KTCZ) is a highly effective broadspectrum antifungal agents. It is used to treat a wide variety of superficial and sys-tematic mycoses [1,2] and has the advantages over other imidazole derivative of pro-ducing adequate sustained release blood level following oral administration [3]. KTCZis poorly – water soluble drug. Oral administration of therapeutic agents represents byfar the easiest and most convenient route of drug delivery, especially in case of chronictherapies [4]. In the case of poorly soluble drugs, the dissolution time in the gas-trointestinal contents may be longer than the transmit time to the intended absorptivesites [5]. Therefore, dissolution of drugs is quit often the rate-limiting which, ulti-mately, controls the bioavailability of the drug [6].
Micelles as drug carriers provide a set of advantages – they physically entrap sparingly soluble pharmaceutics and deliver then to the desired site of action at con-centration that can exceed their intrinsic water solubility and thus increase theirbioavailability [7].
Due to the vital importance of KTCZ determination in pharmaceutical prepara- tions and in biological fluids, several chromatographic [8], spectroscopic [9,10] andelectrochemical methods [11-13] for its quantitative determination have been reported.
However, some of these methods need expensive equipments or are time consuming.
This method is accurate, reproducible and economical which can be useful for theroutine analysis of drugs in laboratory.
In this article we also investigate the effect of polyethylene glycol (PEG) upon the solubility of KTCZ. Because KTCZ is slightly soluble in water.
Experimental: apparatus and reagent
An Elico model SL-164 UV-Vis-spectrophotometer with 1.0 cm matched quartz
cell was used for all spectral and absorbance measurements. KTCZ was obtained asgift sample Glenmark pharmaceutical, Mumbai. Ammonium metavanadate purchasedfrom Loba chemie, and polyethylene glycol obtained from Sigma as a gift sample.
Ammonium metavanadate (0.1mol dm-3): Oxidant solution of ammonium metavanadate (Loba chemie) is used as a primary standard [14]. The solution ofoxidant was prepared by suspending weighed in a standard H SO (AR, BDH) till a clear solution was obtained. The solution so prepared remains stable for 1 month, andhence used as such stock solution. All of the chemicals used in this study were of thehighest purity available and used without further purification.
Ketoconazole: 0.01mol dm-3 stock solution of KTCZ (Glenmark Pharmacetical, Mumbai) was prepared by dissolving about 531 mg of drug in standard sulphuric acidand made up to the mark in 100 ml volumetric flask. The above stock solution wasfurther diluted to get a working standard solution of 1 µg to 500 µg/mL.
Polyethylene glycol: 0.36 mL of PEG dissolve in 100 mL distilled water and diluted to get a 1.25 x 10-4 mol dm-3(CMC of PEG).
Cetyl trimethyl ammonium bromide: 0.364 g of CTAB is dissolve in 100 ml distilled water and diluted the solution to get a 8.24 x 10-5mol dm-3 (CMC of CTAB)solution.
Sodium lauryl sulphate: An aqueous solution of SLS (0.01mol dm-3) was pre- pared by dissolving 288 mg of SLS in a 100 ml calibrated flask with water and dilutedthe solution to get a 2.78 x 10-3 mol dm-3(CMC of SLS) solution.
Solubility determination
Excess KTCZ (50mg) was added to 15 mL of each liquid such as PEG, CTAB,
SLS(at their cmc value), 0.1 mol dm-3 H SO + PEG, 0.1 mol dm-3 H SO + CTAB, 0.1mol dm-3 H SO + SLS taken in a 25 ml stopper flask and the mixtures were shaken 15 hrs at room temperature (28oC ± 1oC) on a rotary flask shaker. 5 ml aliquotwere withdrawn at 1 hr interval and filter immediately using a 0.45 µ disc filter. Thefiltered sample were diluted suitably and assayed for KTCZ by UV-spectrophotomet-ric method. Shaking continued until two consecutive estimation are the same.
Preparation of calibration curve rangingAliquot of standard solution of KTCZ ranging from 0.002 – 0.8 mL were trans- ferred to a series of 10 mL volumetric flask. To that 0.1 mL of ammonium metavanadate(0.01mol dm-3) and 0.125 mL of PEG (0.000125mol dm-3) were successively added,and than added distilled water up to the mark. The absorbance of light pink coloredspecies formed was measured at 375 nm of KTCZ present in the sample solution.
The amount of KTCZ was obtained from its calibration curve.
Assay procedureAt least four tablets of the drug weighed in to a small dish, powdered and mixed well. A portion equivalent 200mg was weighed and dissolved in 1 ml of sulphuric acid and made up to the mark using distilled water. Aliquot of the test solution was dilutedin 10 ml in test tube. An aliquot of diluted drug solution was then treated as describedabove in pure drug.
Results and discussion
Solubility plays a prime role in the dissolution of a drug substance from a solid
dosage form, correlation between solubility and dissolution rate of different drug sub-stance in various media are well established [15-16]. In this study, solubility data willbe used as basis for the development of dissolution medium for KTCZ in future. Thesolubility of KTCZ was determined at 37oC ± 1oC) in different fluids (shown in Table 1).
Table 1. Determination of solubility of ketoconazole in different fluids:
Surfactant greatly increases the solubility of KTCZ. The solubility of KTCZ is increased by 2.51 fold in PEG + purified water system. The surprising increase insolubility of same drug by 7.29 fold is found in acidic PEG i.e. PEG + 0.1 mol dm-3H SO system.
Validation of the methodOptical characteristics such as Beer's law limits, molar absorbitivity and Sandell's sensitivity for KTCZ, are given in Table 1. Beer's law obeyed in the concentrationrange of 1.06µg/mL – 21.25µg/mL which is shown in Fig.1. Data of the regressionanalysis made for the calibration curve are also determined (Table 2). The accuracy and precision of the method made for the calibration checked by analyzing the Beer'slaw range containing the same amount of each drug.
Figure 1 Calibration curve of Ketoconazole
ce 0.16
Concentration (x 10-2 mol dm -3)
Fig. 1. Calibration curve of ketoconazole
Table 2. Results from assay of ketoconazole in tablets
Standard Deviation o f ca libration line LOD and LOQ determinationThe limit of detection (LOD) and the limit of quantization (LOQ) were deter- Where SD is the standard deviation of the absorbance values of the second smallest concentration, m is the slope of the calibration curve [17]. The result obtainedfor pure drug was reproducible with low relative standard deviation (RSD).
The accuracy of the proposed method was checked by performing recovery experiments. For this, a known amount of the pure drug was added to pre-analyzeddosage forms and then determined by the recommended procedure. The result ob-tained in Table 3 showed that the mean recovery and relative standard deviation werein the range of 99.55±0.511 to 100.73±0.777 respectively. These results also sug-gested that there is no interference from the common excipients present in dosageforms.
Table 3. Results from recovery study
Product identification of ketoconazoleKetoconazole is a weak base, virtually insoluble in water, and are ionized only at low acidity. Consequently, Oxidation of these compounds and vanadium species areheavily dependent on acidity.
KTCZ is chiral drugs, and each is used clinically as stereo isomeric mixture. The drug is infact a mixture of the two race mates. i.e. four stereo isomers. In all fourstereo isomers the hydrogen and the dichlorophenyl substituents at the two chiralcenters of the dioxolane ring.
Main oxidation pathways were oxidative scission of the dioxolane ring, oxidative degradation of the piperazine ring and aliphatic oxidation and N-dealkylation at the 1-methyl propyl substituent. As a result of the various oxidation pathways, a very largenumber of products was formed, each representing less than 1-5%. The main oxida-tion product ND-Ketoconazole is characterized.
Mechanism proposed for ketoconazoleIn preliminary experiments, it was observed that by oxidation of V(V) in pres- ence of PEG to acidic solution of KTCZ, at first a pink acidic solution was obtainedwhich become brownish during a few minutes. This is due to oxidation of KTCZ tounstable pink-red keto cation radical KTCZ. On the other hand, it found that the colorof chemically produced cation radical was immediately disappeared in the presenceof V(V) i.e. completely oxidized to products. Based on preliminary tests and massspectra the oxidation product was identified as N-desalkyl-KTCZ and correspondingketone.
Applying the condition for steady state approximation the above scheme leads to [V(OH) HSO +] = K K [VO +] [H+] [HSO –] Rate = K K K [V(OH) HSO +] [HSO –] .(9) [V(V)]T = [VO +]+K K [VO +][H+][HSO –]+K K K [C][VO +] [H+][HSO –] [V(V)]T = ([VO +])+(1+K K [H+][HSO –]+K K K [C][H+][HSO –] Above rate is agreement of experimental finding i.e. rate of oxidation (as well as solubility) is governed by physiochemical properties of drug and pharmacokinetics.
The proposed method is found to be more sensitive and it does not require any
pretreatment of the drug and tedious extraction procedure prior to its determination.
The other ingredients and excipients usually present in pharmaceutical dosage formdid not interfere in the estimation when some commercial dosage forms were ana-lyzed by this method. The accuracy of this method was confirmed by the recoveriesstudies by adding a known amount of the pure drug to the formulations already ana-lyzed by this method. The method was successfully applied to enable estimation ofdrug in pharmaceutical dosage forms at a lower concentration level (each tablet claiming100 mg) and complete with other existing assay methods for routine quality controlanalysis of KTCZ in pharmaceutical formulations.
1. Delgado, J.N., O. Gisvold, W.A. Remers. Wilson and Gisvold's Textbook of Organic
Medical and Pharmaceutical Chemistry, Lippincott Williams & Wilkins, New York, 1998.
2. Odds, F.C., L.J.R. Milne, J.C. Gentles, E.H. Ball. The Activity in vitro and in vivo of a
New Imidazole Antifungal, Ketoconazole. J. Antimicrobial Chemotherapy 6, 97-104 (1980).
3. Farhadi, K., R. Maleki. A New Spectrophotometric Method for the Determination of
Ketoconazole Based on the Oxidation Reactions. Analytical Sciences 17, i867-i870 (2001).
4. Francis, M.F., M. Cristea, F.M. Winnik. Polymeric Micelles for Oral Delivery: Why and
How. Pure & Applied Chem. 76, 1321-1335 (2004).
5. Horter, D., J.B. Dressman. Influence of Physicochemical Properties on Dissolution of
Drug in the Gastrointestinal Track. Adv. Drug Deliv. Rev. 46, 75-87 (2001).
6. Charman, W.N., V.J. Stella. Transport of Lipophilic Molecules by the Intestinal Lym-
phatic System. Adv. Drug Deliv. Rev. 7, 1-14 (1991).
7. Sant, V.P., D. Smith, J.-C. Leroux. Enhancement of Oral Bioavailability of Poorly Water
Soluble Drugs by Poly(ethylene glycol)-block-poly(alkyl acrylate-co-methacrylic acid) Self-Assemblies. J. Controlled Release 104, 289-300 (2005).
8. Low, A.S., J. Wangboonskul. An HPLC Assay for the Determination of Ketoconazole in
Pharmaceutical Preparations. Analyst 124, 1589-1593 (1999).
9. Vojiæ, M.P., G.V. Popoviæ, D.M. Sladiæ, L.B. Pfendt. Protolytic Equilibria in Homog-
enous and Heterogeneous Systems of Ketoconazole and Its Direct Spectrophotometric Deter-
mination in Tablets. J. Serbian Chem. Soc. 70, 67-78 (2005).
10. Sadeghi, M., M. Shamsipur. A New Extractive-spectrophotometric Method for the
Determination of Ketoconazole from Pharmaceutical Preparations. Analytical Lett. 31, 2691-
2705 (1998).
11. Shamsipur, M., K. Fahadi. Adsorptive Stripping Voltametric Determination of
Ketoconazole in Pharmaceutical Preparation and Urin Using Carbon Paste Electrode. Analyst
125, 1639-1643 (2000).
12. Shamsipur, M., K. Farhadi. Electrochemical Behaviour and Determination of
Ketoconazole from Pharmaceutical Preparations. Electroanalysis 12, 429-433 (2000).
13. Shamsipur, M., F. Jalali. Preparation of Ketoconazole Ion Selective Electrodes and Its
Application to Pharmaceutical Analysis. Analytical Sciences 16, 549-552 (2000).
14. Vogel, A.I. A Text-Book of Quantitative Inorganic Analysis, Including Elementary
Instrumental Analysis. Wiley, New York, 1968.
15. Nicklasson, M., A. Brodin. Studies on the Relationship between Solubility and Intrin-
sic Rate of Dissolution as a Function of pH. Acta Pharmaceutica Suecica 18, 119-128 (1981).
16. Chowdary, K.P.R., S.K.S. Rao. A Study on the Development of Dissolution Medium
for Itraconazole. Indian Drugs 37, 291-294 (2000).
17. Comoglu, T., N. Gonul. Quality Control Studies on Conventional Carbamazepine Tab-
lets Available on the Turkish Drug Market. Turkish J. Med. Sci. 35, 217-221 (2005).
18. Ephraim, F. A Text-Book of Inorganic Chemistry. Gurney and Jackson, London, 1934.
* Neeti NEMA,
Nimesh SINGH,
Prof. Archna Pandey (corresponding author)
Dr. Hari Singh Gour University,
E-Mail: [email protected]

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