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1 Page6460 Indo American Journal of Pharmaceutical Research, 2013 ISSN NO: Journal home page: INDO AMERICAN JOURNAL OF PHARMACEUTICAL RESEARCH PHASE SOLUBILITY STUDY ON MUSCLE RELAXANT METAXALONE DRUG Vivek R. Bhavsar 1, Prabodh V. Sapkale 2, Tushar D. Fegade 2 1 Analytical Solution Pvt. Ltd., Mumbai, Maharashtra, India 2 SES, Arunamai College of Pharmacy, Jalgaon, Maharashtra, India ARTICLE INFO Article history Received 29/06/2013 Available online 31/08/2013 Keywords Solubility, Intrinsic Solubility, Phase Solubility, Metaxalone Drug. ABSTRACT IUPAC (The International Union of Pure and Applied Chemistry) defines solubility as the analytical composition of a mixture or solution which is saturated with one of the components of the mixture or solution, expressed in terms of the proportion of the designated component in the designated mixture or solution Solubility can further be defined in a more specific manner, like un-buffered, buffered and intrinsic solubility. Un-buffered solubility means the solubility of a saturated solution of the compound at the final ph of the solution. As a qualitative phenomenon, solubility may be defined as the spontaneous interaction of two or more substances to form a homogenous molecular dispersion. A saturated solution is one in which the solute is in equilibrium with the solvent. The solubility of a drug is expressed in terms of various words such as parts, percentage, molarity, molality, volume fraction, mole fraction. Metaxalone is a drug approved by FDA in 1962 as an adjunct to rest, physical therapy and other measures for the relief of discomforts associated with acute painful musculoskeletal conditions. Its exact mechanism is not known, but it may be due to general central nervous system depression. It is considered to be a moderately strong muscle relaxant. Corresponding author Vivek R. Bhavsar Analytical Solution Pvt. Ltd. Mumbai, (MS), India. prabodhsapkale@yahoo.com Contact Please cite this article in press as Vivek R. Bhavsar et.al. Phase solubility study on muscle relaxant metaxalone drug. Indo American Journal of Pharm Research.2013:3(8). Copy right 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. INTRODUCTION

2 Page6461 Metaxalone is a drug approved by FDA in 1962 as an adjunct to rest, physical therapy and other measures for the relief of discomforts associated with acute painful musculoskeletal conditions. Its exact mechanism is not known, but it may be due to general central nervous system depression. It is considered to be a moderately strong muscle relaxant. Metaxalone is marketed under the brand name skelaxin by king pharmaceuticals. The structure of metaxalone is as follows and its IUPAC name is- 5-[(3,5-dimethylphenoxy)methyl]-1,3-oxazolidin- 2-one. The metaxalone have a various synonyms as Zorane, AHR-438, Skelaxi. The molecular formula of metaxalone is C 12 H 15 NO 3 and molecular weight is 221gm/mole. It is white crystalline powder.[1] Figure 1: Structure of Metaxalone As per the dosage regimen is concerned For an adult, metaxalone is required to be administered 800 mg daily, 3-4 times a day for its intended therapeutic effect. Initially, metaxalone was marketed as 400 mg oral tablet. Peak plasma concentration of metaxalone occurs approximately 3 hours after Administration of 400 mg oral dose of metaxalone under fasted condition. Thereafter, metaxalone concentration declines log-linearly with a terminal half-life of 9.0 ± 4.8 hours. When metaxalone was administered in double dose quantity of 800 mg resulted in roughly proportional increase in metaxalone exposure as indicated by peak plasma concentration (Cmax) and area under the curve (AUC). Metaxalone has very limited solubility in water (0.36 mg/ml)[determined experimentally] which is the major factor contributing for the low bioavailability of the drug which ultimately results in slow building of therapeutic concentration within the blood and postponed the onset of action to 3 h after oral administration as stated earlier. Also metaxalone profile shows that it has good lipophilicity (logp~3.8) which indicates that the drug gets distributed in tissue to a great extent. Thus, metaxalone is a drug with low solubility and high permeability which is the characteristic feature of BCS class II drugs. BCS provides a guiding tool for formulation scientist for recommending a strategy to improve the efficiency of drug development by proper selection of dosage form and bioequivalence test to recommend the class of dosage form. Objectives and Concept of BCS The objectives of the BCS are: To improve the efficiency of the drug development and review process by recommending a strategy for identifying expendable clinical bioequivalence test. To recommend a class of immediate-release (IR) solid oral dosage forms for which bioequivalence may be assessed based on in vitro dissolution tests. To recommend methods for classification according to dosage form dissolution along with the solubility permeability characteristics of the drug product. The BCS, which is based on scientific principles, presents a new paradigm in bioequivalence. According to the tenets of the BCS, certain drug products can be considered for bio-waivers (i.e., product approval based on in vitro dissolution tests rather than bioequivalence studies in human subjects). At first, biowaivers were only applied to scale-up and post approval changes (SUPAC), but later the biowaiver principle was extended to the approval of new generic drug products. As a result, unnecessary human experiments can be avoided, and the cost of developing generic products can be significantly lowered [2]. It provides drug designers an opportunity to modify the structure or physicochemical properties of lead candidates to achieve better deliverability [3]. Classification System of BCS

3 Page6462 The BCS is a scientific framework for classifying a drug substance on the basis of their aqueous solubility and intestinal permeability [4]. It allows for the forecasting of in vivo pharmacokinetics of oral immediate-release (IR) drug products by classifying drug compounds into four classes (Table 1) based on their solubility related to dose and intestinal permeability in combination with the dissolution properties of the dosage form. This classification of biopharmaceutical classification system is associated with a drug dissolution and absorption model, which identifies the key parameter controlling drug absorption as a set of dimensionless numbers [5, 6]. Sr. No. Class Solubility Permeability 1 I High High 2 II Low High 3 III High Low 4 IV Low Low MATERIALS AND METHODS Metaxalone (Angelini pharmaceuticals ltd.), β-cyclodextrin (RLFC, Mumbai), (2- hydroxy propyl)-βcyclodextrin (Kleptose HPB Rosequett Ltd.), methanol-ar (RLFC, Mumbai). Phase solubility technique The phase solubility technique involves adding an equal weight (in considerable excess of its normal solubility) of the compound to be complexed into each of several vials or ampoules. A constant volume of solvent is added to each container. Successively increasing portions of the complexing agent are then added to the vessels. The vessels are then closed and the contents brought to solubility equilibrium by prolonged agitation at constant temperature. The solution phases are then analyzed for total solute content. A phase diagram is constructed by plotting the molar concentration of dissolved solute, found on the vertical axis, against the concentration of complexing agent added on the horizontal axis. Two general types of phase solubility profiles are generated; Type A where soluble complexes are formed and Type-B where complexes of limited solubility are formed [7]. Figure 2: Possible types of phase solubility diagrams. In Type-A diagrams, an increase in solubility of the compound occurs as the amount of complexing agent increases. Soluble complexes are formed between the compound and the complexing agent, thereby increasing the total amount of compound in solution. Depending on the nature of the complexes formed, the diagram can be linear, A L, or show curvature in a positive, A P, or negative, A N, fashion (Figure 2). Linear diagrams are formed when each complex contains only one molecule of complexing agent. When more than one molecule of complexing agent is found in the complex, an A P -type diagram is formed. A N type diagrams are uncommon but

4 Page6463 may result if self-association is present or high concentrations of complexing agent cause alterations in the nature of the solvent. Type B diagrams are observed when complexes of limited solubility are formed. In figure2, segment xy in curve BS shows the formation of a complex that increases the total solubility of the compound. This is similar to a Type A diagram. At point y, however, the solubility of the complex is reached and as additional compound goes into solution, some solid complex precipitates. At point z, the excess solid compound added to the vials has been consumed by this process. Further addition of complexing agent beyond point z results in depletion of the compound from solution by complex formation. Curve BI is interpreted in a similar manner except that the complex formed is so insoluble that no increase in solubility is observed. The stoichiometry of the complexes can often be determined from the ascending and descending portions of these diagrams if certain assumptions can be made. If a 1:1 complex is formed, the association constant K a:b can be determined from the slope of the initial linear portion of the phase solubility curve, and the intrinsic solubility of the compound, S 0 using Equation (1). Where, I o is intrinsic solubility. K= Slope/ I o (1- slope) [1] Preparation of Stock Solution A stock solution of metaxalone (200 ppm) was prepared by dissolving 20 mg of metaxalone in 20 ml of methanol in a 100 ml volumetric flask and the volume was adjusted to 100 ml with sufficient quantity of double distilled water. Determination of intrinsic solubility of metaxalone by shake flask method Pipette out 10.0 ml distilled water in a 50 ml conical flask. Add Excess quantity of metaxalone (100 mg) in the distilled water. Place the conical flask in rotary shaker and allow the conical flask to rotate at RPM for 48 hrs; so that the solvent get completely saturated with metaxalone. Filter out the content using whatman filter paper (size41). Now pipette out 1 ml of filtered solution; transfer into 10 ml volumetric flask and make up the volume using distilled water. Determine the absorbance of resultant solution at nm using double beam spectrophotometer. Determine the concentration of metaxalone in solution by interpolating the absorbance of resultant solution on graph of calibration curve of metaxalone. Considering the dilution factor express the concentration of metaxalone in mg/ml as intrinsic solubility.[8] Phase solubility study Different molar solutions of HP-β-CD (5,10,15,20,25,30 mm) and β- CD (2,4,6,8,10 mm) were prepared by diluting required quantity of HP-β-CD and β- CD respectively in double distilled water. 5 ml of molar solution was withdrawn from different molar solution and transferred to respectively labeled 50 ml conical flask. Excess quantity of metaxalone was added to each conical flask. The conical flask were shifted in rotary shaker and allowed to Rotate at RPM for the period of 48 hrs. After 48 hrs; the flasks were removed and filter the contents to respective labelled vials of molar solutions of HP-β-CD and β-cd. 1.0 ml of filtered solution was pipette out and transfered into 10.0 ml volumetric flask and make up the volume using double distilled water. The absorbances of resultant solutions were recorded at nm using double beam spectrophotometer. The concentration of metaxalone in solution was determined by interpolating the absorbance of resultant solution on graph of calibration curve of metaxalone. Considering the dilution factor; the concentration of metaxalone was expressed in moles per liter. The graph of molar concentration of drug verses molar concentration of polymer

5 Page6464 absorbance was plotted. The slope and y-intercept (molar intrinsic solubility) values were Determined. The stability constant for metaxalone- inclusion complex with HP-β-CD and β-cd was calculated by using the following equation.[9] K= m/ Io (1-m) Where, K- is stability constant of complex, I0- is y-intercept, m-is the slope of line Table 1: Absorbance value of metaxalone in different concentration along with polymers Sr. No. CONC. Of HPBCD (mm) Conc. In ppm at Solubility in mg/ml Mol wt of drug Molar conc of drug Absorbance at nm Concentration Figure 3: Phase solubility of metaxalone drug.

6 Page6465 RESULT AND DISCUSSION Determination of intrinsic solubility of metaxalone: Table 2: Determination of aqueous solubility of metaxalone Sr. No. Absorbance at nm Concentration in µg/ml Solubility in mg/ml Average solubility + SD ± The intrinsic aqueous solubility of metaxalone was found to be mg/ml. Phase solubility study result Phase solubility study for metaxalone, β-cyclodextrin and hydroxyl propyl-β-cyclodextrin Table 3: Phase solubility study of metaxalone and HP-β-CD Sr. No. Conc. Of HP-β-CD (mm) Molar conc. of Drug (M) ± ± ± ± ± ± ±2.07 All values are determined as Mean ± SD (n=3) Table 4: Phase solubility study of metaxalone and β-cd Sr. No. Conc. Of β-cd (mm) Molar conc. of Drug (M)

7 Page6466 Figure 3: Effect of HP- β-cd (5-30 mm) on the UV spectrum of metaxalone Figure 4: UV spectrum of 50 mm HP-β-CD in a aqueous solution

8 Page6467 The phase solubility curve of metaxalone with HP-β-CD was determined by plotting the graph of molar concentration of HP-β-CD with molar concentration of metaxalone found in the solution. The graph is shown as Figure 5. Figure 5: Phase solubility study of metaxalone and HP-β-CD in aqueous solution CONCLUSION Phase solubility diagram indicate formation of stable and effective complex of metaxalone with hydroxyl propyl-β-cyclodextrin resulting in enhancing solubility of metaxalone from 36 ppm to 137 ppm. Hence we can say phase solubility is a great tool for increasing the solubility without affecting their bioavability. REFERENCES 1. Accessed on 10/11/ Thomas VH, Bhattachar S, Hitchingham and Zorcharski P. The road map to oral bioavailability: An industrial perspective. Expert opin. 2006; 2(4): Rawat A, Verma S, Kaul M, Kaul S. Solid dispersion: A strategy for solubility enhancement. Int. J. Pharm. Tech. 2011; 3(2): Raymond CR, Paul JS, Paul JW. Handbook of pharmaceutical excipients. Royal pharmaceutical society, London UK 2003; (3): , , , Lidenberg M, Kopp S, Dressman JB. Classification of orally administered drug on the world health organization model list of essential medicines according to the biopharmaceutics classification syatem. Eur. J. Pharm. Biopharm. 2004; 58: Lipinski CA, Borchardt RT, Kerrns EH, Wang B, Thakler DR. Solubility in water and DMSO: Issues and potential solutions. A. Assoc. pharm. Sci. 2004; Waterbeemd HV, Lennernas H, Artursson P. Drug bioavailability: Estimation of solubility, permeability, absorption and bioavailability. Wiley-VCH, Weinheim 2003; Gibson M. Pharmaceutical Preformulation and Formulation: A practical guide from candidate drug selection to commercial dosage form. Interpharm, USA 2009; (1):

9 Page Tablet C, Matai I, Hillerbrand M. Determination of stoichiometry of cyclodextrin inclusion complexes by spectral method: Possibilities and limitation. Stoichiometry and Reasearch- The Importance of Quality in Biomedicine 2012; Submit your next manuscript to IAJPR and take advantage of: Access Online first Double blind peer review policy No space constraints Rapid publication International recognition Submit your manuscript at: