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Application of Lactobionic Acid and Nonionic Surfactants As Solubilizing Agents for Parenteral Formulation of Clarithromycin

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Application of Lactobionic Acid and Nonionic Surfactants As Solubilizing Agents for Parenteral Formulation of Clarithromycin View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Directory of Open Access Journals Advanced Pharmaceutical Bulletin, 2012, 2(1), 37-42 doi: 10.5681/apb.2012.006 http://apb.tbzmed.ac.ir/ Application of lactobionic acid and nonionic surfactants as solubilizing agents for parenteral formulation of clarithromycin Parvin Zakeri-Milani1,2, Niaz Mousavian-Fathi1,3, Saeed Ghanbarzadeh1,4, Mohammad-Hosein Zarrintan1, Hadi ٭Valizadeh1,5 1 Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. 2 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 3 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran. 4 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 5 Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran. A R T I C L E I N F O A B S T R A C T Article Type: Purpose: The purpose of this paper is to enhance the solubility of clarithromycin (CLR) Research Article using nonionic surfactants and some type of acids for preparation of the new formulations. Methods: Myrj 52 and chremophor (2.5 and 5% w/v) were used in two Article History: concentrations. To investigate solubility, the formulations were shaken for 48 hours at Received: 7 Jan 2012 Accepted: 27 Jan 2012 room temperature. For stability test, lyophilized samples were maintained in ePublished: 15 Feb 2012 refrigerator at 4° C, and in oven at 40° C. Drug analysis was performed by reverse phase high performance liquid chromatography (HPLC) with ultraviolet detection. Keywords: Results: Solubility tests indicated that lactobionic acid was the most effective to Clarithromycin increase clarithromycin solubility and chremophor showed higher enhancing effect than Lactobionic acid myrj 52 on CLR solubility. The stability tests results also confirmed that shelf-lives of Nonionic surfactants all formulations have been the equivalent to 24 months. Conclusion: On the whole, Solubility Parenteral formulations described in this article may be very suitable for industrial-scale manufacturing and clinical application. Introduction Clarithromycin is a relatively new, second-generation, parenteral formulation of clarithromycin. However, the semi synthetic macrolide antibiotic with a methoxy main problem related with clarithromycin intravenous group (OCH3) attached to the C6 position of form is its practical insolubility in water. erythromycin. This derivatization makes clarithromycin Clarithromycin has the dimethylamino moiety as the more acid stable than erythromycin. 1,2 Clarithromycin only ionizable group (pK8.8) and hence its aqueous has broad-spectrum activity against gram-positive and solubility at pH 7.0 is only about 500 µg/ml. 2,10 Using gram-negative aerobes, atypical bacterial pathogens of binary systems with a hydrophilic carrier by mixing, the respiratory tract, mycobacterium species, melting or solvent methods emulsion formulations for Legionella and helicobacter pylori. 3 Many dosage its IV use have been studied. However, leaving residual forms of clarithromycin, such as immediate and solvent, thermal degradation of clarithromycin during extended release tablets, capsules, dry suspensions, thermal sterilization and complication of these liposome-encapsulated, microspheres, cyclodextrin- processes has limited the application of these methods. compressed and IV formulation have been developed 2,10 Therefore it is necessary to develop a new due to its wide antibacterial spectrum. 2,4-9 Nevertheless formulation to improve its solubility for intravenous considering adverse effects of oral dosage forms such administration of clarithromycin. 11 We hypothesized as gastrointestinal disorders and low bioavailability that surfactants and gluconic acids can enhance which doesn’t exceed 55%, and the existence of some clarithromycin solubility. 10 Based on this hypothesis situations such as unconscious patients for whom the myrj52 and chremophor (in different proportions) and only usable dosage form is parenteral form and also the lactobionic acid were investigated and results were absence of generic intravenous dosage form in Iran, compared and the best formulations were reported. there is considerable interest in the development of a *Corresponding author: Hadi Valizadeh (PhD), Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. 51664. Tel: +98 411 3392649, Fax: +98 411 3344798, E-mail: [email protected] Copyright © 2012 by Tabriz University of Medical Sciences Zakeri-Milani et al. Materials and Methods drug analysis. The mobile phase consisted of acetonitrile- sodium dihydrogen phosphate (2:3 v/v) Materials containing phosphoric acid (3M) and NaOH (1N) to Clarithromycin (Elder Nerul, Pawane and Patalg, adjust the pH on 4.5. The flow-rate was 2 ml/min and India), Lactobionic acid (Sigma – Aldrich, Co. St. the detection wavelength was set at 205nm. Column Louis , MO , USA), Chremophor (BASF Florham (Shimadzu C18:250mm×4.6mm, 4µm) temperature Park, New Jersey), Myrj 52 (Atlas San Diego, USA ), was maintained at 59°C using oven (Memmert, Anhydride citric acid(Merck Dermstadt, Germany), Germany) and the injection volume was 20µL. Sulfuric acid (Merck Dermstadt, Germany), Stearic acid (Merck Dermstadt, Germany), Boric acid (Merck Method validation Dermstadt, Germany), Hydrochloric acid (Merck In this study a reverse phase HPLC method with Dermstadt, Germany), Phosphoric acid (Merck ultraviolet detection was used. Standard solutions of Dermstadt, Germany), Salicylic acid (Merck 3.125 to 50 mg/ml were prepared in water, and linearity Dermstadt, Germany), NaOH (Merck Dermstadt, range and correlation coefficient were obtained. To Germany), Sodium dihydrogen phosphate (Merck evaluate the inter-assay precision and accuracy, Dermstadt, Germany), Acetonitril (Merck Dermstadt, samples were analyzed for 3 consecutive days, while Germany), Tartaric acid (Seelze- Hannover Riedel _ intra-assay precision and accuracy were evaluated Dehaen AG , Germany). through analysis of samples at three different concentrations in the same run. Relative standard Formulation deviation (RSD) and the accuracy were calculated To increase clarithromycin solubility in water to using the experimental concentration and the nominal prepare an injectable solution, above mentioned acids concentration for each sample. were used. Results indicated that lactobionic acid is the only acid which can improve drug solubility. Nonionic Stability tests surfactants, myrj 52 and chremophor also were used for To investigate the short-term storage stability of solubilization. To produce 5 formulations, different clarithromycin in formulations and determine the shelf concentrations of two surfactants were selected, added life, at least 6 vials of each formulation were kept for 6 to appropriate amount of double distilled water and month in undesirable conditions including constant were sonicated (Julabo USR 3 Labortechnik, Germany) relative humidity of 75% and temperature of 40◦ C until complete dissolution. Then 500 mg of which equals maintaining for 2 years in ambient clarithromycin was added up and agitation was conditions. Other lyophilized formulations were kept in continued for 15 min. Acid solution was then added -20◦ C. For stability study of newly prepared and ready and after 5 minutes of stirring, pH was measured to use injection solution of formulations, a sample of (Metrohm, Switzerland). Acid addition was continued each formulation was tested over 120 h at 4◦ C. until a clear solution was achieved. However to For determination remained drug in formulations, increase stability the pH was kept above 4.8. pH of monthly a vial from samples in oven and freezer was solutions were adjusted using phosphoric acid 85% and taken and was brought to volume 10ml with double NaOH 1N in the range of 5 to 6.5. Then the solutions distilled water. Samples were shaken and sonicated for were filtered through the 0.22µ membrane filter. To 5 minutes and injected to HPLC column in triplicate. prepare samples for stability tests, 20 vials of each This test was also performed for ready to use solution formulation were prepared. The samples were dried and within 5 days. Monthly a calibration curve was taken. lyophilized for 48 hours in the freezer (- 20°C), and then were maintained in refrigerator at 4°C. Differential Scanning Calorimetry (DSC) Differential Scanning Calorimetry is a rapid and exact Solubility study way to examine drug and excipient compatibility and CLA solubility samples were prepared in glass tubes at provides the most information about possible serial concentrations for all five solvent systems interactions. Samples (5 mg) were sealed in aluminum developed. For each system ten glass tubes with pans and heated at a rate of 20◦ C per minute from 30◦ C different concentration of drug were prepared. Then the to 300◦ C (DSC-60, Shimadzu, Japan). Thermal samples were shaken for 48 hours at room temperature. behaviors of clarithromycin and exipients, the complex The first tube in each series in which the fine un- and the physical mixture of them were determined and dissolved drug particles were seen, was detected by compared. visual inspection and finally the range of drug solubility were determined. Results To examine the effect of different acids on CLR Drug analysis solubility, various acids such as lactobionic acid, A reverse phase high performance liquid anhydride citric
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