Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore s3

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1 Name of the candidate and SHAH JAYESH PRAVIN address BAPUJI PHARMACY COLLEGE (in block letters) S.S. LAYOUT, SHAMANUR ROAD DAVANGERE – 577 004

2 Name of the institution BAPUJI PHARMACY COLLEGE

3 Course of study and subject M. PHARM

(INDUSTRIAL PHARMACY)

4 Date of admission to the course 30/09/2010

5 Title of topic SOLUBILITY BEHAVIOR OF ARIPIPRAZOLE IN THE SOLVENT BLENDS OF DIFFERENT POLARITY : SOLUBILITY PARAMETER APPROACH 6. BRIEF RESUME OF THE INTENDED WORK

6.1 Need for study

The nature of liquid mixtures may be interpreted in terms of molecular interactions broadly

classified as either “reactive” (involving relatively strong ‘chemical’ forces such as complex formation,

etc.) or “non-reactive” (involving relatively weak ‘physical’ or van der Waals forces). Solution

nonideality can of course be best explained if both ‘chemical’ and ‘physical’ forces are considered; the

true situation is generally intermediate between these two extremes. Most of liquid pharmaceuticals

consist of one or more solids dissolved in a liquid or a mixture of liquids. The solubility of the solids

varies with the composition of the solvent mixture; therefore, information that would allow the

pharmacist to control the solvent properties of a mixture of liquids would be great value.1

The most frequently encountered difficulty in the preparation of solutions is the solubility of the

drug. The solubility of the solid varies with the composition of the solvent mixtures. Therefore,

solubility knowledge is important to the pharmacists for it permits in choosing the best solvent medium

for a drug or a combination of drugs. Thus solubility studies help in overcoming certain difficulties

that arise in the preparation of pharmaceutical solutions. Lipophilic solvents are required for lipid

soluble drugs that are to be administered in soft gelatin capsules, suppositories, topical preparations,

and injections. In these circumstances, the most efficient, non toxic solvent may still not be the best for

the purpose in mind. Therefore, the ability to predict solubility is important in order to select the

solvent that can give the appropriate bioabsorption response. The solubility phenomenon is one of the

least understood of all the physicochemical properties particularly with reference to pharmaceutical

solutions.

Aripiprazole is 7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-1,2,3,4-tetrahydroquinolin-2-

one a typical antipsychotic medication used for the treatment of schizophrenia and falls in BCS class II

drugs. It has also recently received FDA approval for the treatment of acute manic and mixed episodes

associated with bipolar disorder.2 Aripiprazole tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20

mg, and 30 mg strengths. The solubility of aripiprazole in water is about 0.77 mg/100 ml, i.e. 0. 007 mg/ml. This solubility is, of course, not sufficient to achieve the therapeutically required dosage for liquid dosage forms. Upon standing, supersaturated solutions precipitate aripiprazole crystals, so that they are unsuitable as ready-to-inject injection solutions and liquid orals.

The poor solubility and therapeutic importance make aripiprazole suitable for the present study.

6.2 Review of the study

Solutions are categorized as ideal and non-ideal solutions.3 An ideal solution is the one in which the solute-solvent interactions are of same magnitude as that of solvent-solvent and solute-solute interactions. Any deviation from ideal solution behavior is described as non-ideal (or regular). Most of the pharmaceutical solutions are non-ideal because these systems are polar involving self-association of solute or solvent, salvation of solute by solvent molecules or complexation of two or more species in the solution. Attempts were made in this direction on a few drugs such as pimozide4 and celecoxib5 to explore their solubility behaviour. The offshoot of these theories is the concept of solubility parameter.

Karanth and Joysula studied the correlation between solubility parameter and anti bacterial activity of amoxicillin trihydrate. Solubility parameter of the drug was evaluated in blends of ethyl acetate-propylene glycol and water-propylene glycol in different ratios. The results obtained were compared with values obtained using molar volume method and found that ethyl acetate-propylene glycol (75:25) gave maximum solubility.6

An equation describing solubilization in aqueous systems by co-solvents was developed by treating a mixed solvents as a linear combination of its components. This equation can successfully explain both the exponential increases and decreases in aqueous solubility that are frequently observed with the addition of cosolvent.7

The solubility of benzoic acid and esters of p-hydroxy benzoic acid were determined in a series of n-alkanols, and Hildebrand’s solubility parameters were assigned to these compounds. The experimental results were compared with the theoretical solubility calculated from the Hildebrand equation for regular solution. Fair agreement between experimental and theoretical values was found for methyl and p-benzoic acids.8

Sathesh babu et al. determined the solubility of meloxicam in polyethylene glycol 400, water, ethanol, propylene glycol, phosphate buffer pH 7.4, Tween 80 and Brij 35 in order to understand the nature of drug–vehicle interactions. Meloxicam exhibited highest solubility (7 mg/ml) in polyethylene glycol 400 due to possible hydrophobic interaction of meloxicam with polyethylene chains. The solubility of meloxicam is marginally enhanced in surfactant systems (Tween 80 and Brij 35) at concentrations higher than cmc, proving the micellar solubilization. These interactions are allowed to give nature of interactions, by studying the graded relationship between polyethylene glycol 400–other vehicles. Meloxicam solubility is highest (12 mg/ml) in polyethylene glycol 400–phosphate buffer in the ratio of 40:60. This vehicle may have the matching polarity as that of meloxicam. These results were confirmed by the quantifying effects of cosolvent using Setschenow equation. The functional groups in meloxicam have definite role in the solubilization and hydrophobic interaction is predominant with polyethylene glycol 400 vehicles.9

Neelam Seedher et al. examined the solubility enhancement of four cox-2 inhibitors using a series of pure solvents and solvent mixtures. Water, alcohols, glycols, glycerin, and PEG 400 were used as solvents and water-ethanol, glycerin-ethanol, and PEG-ethanol were used as mixed solvent systems. It was found that the greater the difference in the polarity of the two solvents in a given mixed solvents, the greater was the solubilization power. However, in a mixed solvent system, the solubilization power could not be related to the polarity of the drugs. Significance of the solubility data in relation to the development of formulations had been studied.10

6.3 Objectives of the study

The study is aimed at achieving the following:

a) To determine the solubility behavior of aripiprazole in the context of available theories of

solutions namely ideal, regular, and irregular solutions. These studies establish a relationship

between chemical properties of aripiprazole and solubility.

b) To determine the solubility parameters of aripiprazole, this may help in selecting the right

solvent and cosolvent to get an optimum level of solubility.

Material and methods

7.1 Source of data The physicochemical properties of aripiprazole, solvents, and other chemicals will be collected 7. from the literature, internet journals, CIMS, MIMS, and ORG-IMS and other sources from the library.

7.2 Methods of collection of data (including sampling procedure, if any)

a) Spectrophotometric method of analysis for the estimation of aripiprazole in suitable solvents

will be developed.11

b) Saturated solution of the aripiprazole will be prepared in binary solvent systems at 25 oC.

c) Solubility will be determined in various ways.

d) Solubility parameter and molar volume values will be determined using theoretical (Hoy’s 12,

Fedors13, and Van Kreevelon1 constants.) and experimental methods.

e) Solubility of the drug will be expressed by various ways.

f) Statistical analysis of data will be obtained from the results.

7.3 Does the study require any investigation or intervention to be conducted on

Patients or other human or animals?

No. Not applicable

7.4 Has ethical clearance been obtained from your institution in case of 7.3?

No. Not applicable

List of References

1. Barton AFM. Handbook of solubility parameters and other cohesion parameters. 2nd ed. New York: CRC Press;160-83. 8. 2. www.drugbank.com:23/05/2011

3. Martin A, Bustamante P, Chun AHC. Physical Pharmacy. 4th ed. New Delhi: B.I. Waverly Pvt

Ltd;1997.

4. Thimmasetty J, Subrahmanyam CVS, Sathesh Babu PR, Maulik MA, Viswanath BA. Solubility

behaviour of pimozide in polar and nonpolar solvents: Partial solubility parameters approach. J

Sol Chem, 2008, 37: 1365–78.

5. Thimmasetty J, Subrahmanyam CVS, Viswanath BA, Sathesh Babu PR. Solubility parameter

estimation of celecoxib by current methods. Asian J Res Chem, 2009, 2(2), 188-95.

6. Karanth H, Joysula VR. Studies on solubility parameter of amoxicillin trihydrate: influence on in

vitro release and anti bacterial activity. Ind J Pharm Sci 2005; 67(3):342-5.

7. Yalkowsky SH, Joseph TR. Solubilization by co-solvents I: organic solutes in propylene glycol-

water mixtures. J Pharm Sci 1985; 74(4):416-21.

8. Restaino FA, Martin AN. Solubility of benzoic acid and related compounds in a series of n-

alkanols. J Pharm Sci 1964; 53(6):636-9.

9. Sathesh Babu PR, Subrahmanyam CVS, Thimmasetty J, Manavalan R, Valliappan K. Solubility

of meloxicam in mixed solvent systems. Ethiop Pharm J 2007; 25:23-8.

10. Seedher N, Bhatia S. Solubility enhancement of cox-2 inhibitors using various solvent systems.

AAPS Pharm Sci Tech 2003; 4(3):1-9.

11. Kalaichevi R, Thangabalan B, Srinivasarao D, Jayachandran E. UV Spectrophotometric

determination of aripiprazole in bulk and pharmaceutical formulation, E J Chemistry, 2009,

6(S1), S87-S90.

12. Hoy KC. New values of the solubility parameters from vapour pressure data. J Paint Technol

1970; 41:76-118.

13. Fedors RF. A method of estimating both solubility parameters and molar volumes of liquids. Polym Eng Sci 1974; 14:147-54.

9. Signature of the Candidate

10. Remarks of the Guide 11. Name and Designation of

(In block letters)

11.1 Guide Dr. J. THIMMASETTY M. Pharm, Ph.D.

SG Lecturer

Department of Industrial Pharmacy

Bapuji Pharmacy College, Davangere.

11.2 Signature

11.3 Co-Guide (if any)

11.4 Signature

11.5 Head of Department Dr. J. THIMMASETTY M. Pharm, Ph.D.

Head of the Department of Industrial Pharmacy

Bapuji Pharmacy College, Davangere.

11.6 Signature

12. 12.1 Remarks of the Principal

12.2 Signature