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6.
BRIEF RESUME OF THE INTENDED WORK
6.1 Need for study
Solubility plays a vital role in the drug effectiveness and is applicable to dosage forms
administered by different routes. It also possesses a major challenge for developing new pharmaceutical
products, since nearly 60% of the drugs obtained directly from synthesis are either insoluble or poorly
soluble in water.1 The nature of solvent - cosolvent interactions and the composition of the solvent
mixtures lead to variation in the solubility of a solute in the vehicle. Accordingly pharmacist controls the
properties of mixture of liquids. Sugar vehicle is an example of a cosolvent system, which significantly
increases or decreases the solubility of a solute.2
Solubilization technique is usually applied in order to prepare liquid dosage formulations. The
most fruitful means of increasing the solubility is to develop an aqueous vehicle, which closely matches
the polarity of the drug. If the drug is a weak electrolyte this can usually be done by controlling pH of the
solvent. For many drugs, alteration of pH cannot provide the desired increase in solubility. For these
drugs, the use of one or more solubilizing techniques, such as micellization, complexation, and
cosolvency, can often provide an effective means of increasing solubility.3 The mechanisms of
solubilization by surfactants and complexing agents are fairly well understood. These combinations
minimize the excessive use of additives and avoid their undesirable side effects.4
Carvedilol is (l- (9H-carbazol-4-yloxy)-3- [[2-(2-methoxyphenoxy) et}hyl] amino] - 2-propanol)
suitable for the treatment and prophylaxis of circulatory and cardiac disorders such as hypertension and
angina pectoris. Carvedilol is available as 3.125, 6.5, 12.5 and 25 mg tablets in the market. The solubility
of carvedilol in water is about 0. 2 mg/100 ml, i. e. 0. 002 mg/ml, with a pH value of 6.1. This solubility
is, of course, not sufficient to achieve the therapeutically required dosage for liquid oral form or for an
injection solution in the order of several mg/ml. Upon standing, supersaturated solutions precipitate
carvedilol crystals after a short period, so that they are unsuitable as ready-to-inject injection solutions and
liquid orals. An increase in the acidity to pH values of 1 to 3 indeed prevents the crystallization of the
carvedilol and increases the dissolved amount of the active substance, but leads to an intolerance of the
solutions by veins. Moreover, decomposition products form there from after a short period. These
decomposition products also mean that such a solution cannot be used for injection and liquid oral.5
By observing the above points, carvedilol appears as a suitable candidate to make into liquid
dosage forms.
6.2 Review of the study
Solutions are categorized as ideal and non-ideal solutions.6 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 paracetamol7 and carbamazepine to
explore their solubility behaviour.8 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 acetatepropylene 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.9
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.10
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.11
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.12
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.13
6.3 Objectives of the study
The study is aimed at achieving the following:
a) To enhance the solubility of carvedilol using different solubilization techniques.
b) To develop formulation in order to provide carvedilol or its pharmacologically harmless salts as
solutions having therapeutically relevant concentrations, with the dosage forms being stable on storage.
7.
Material and methods
7.1 Source of data
The physicochemical properties of drug, solvents, surfactants, buffers, and cyclodextrins will be
collected from the literature, internet journals, CIMS, MIMS, and ORG-IMS and other sources from the
library.14
7.2 Methods of collection of data (including sampling procedure, if any)
a) Spectrophotometric method of analysis for the estimation of carvedilol in suitable solvents will be
developed.
b) Saturated solution of the drug will be prepared in binary solvent system at 25oC.15
c) Solubility will be determined in various ways.
d) Solubility parameter and molar volume values will be determined using Hoy’s16 and Fedors17
constants.
e) Solubility of the drug will be improved by various ways.
f) Liquid oral and injection dosage forms will be formulated.13
g) The prepared formulations will be subjected to evaluation including stability studies.
h) 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
8.
List of References
1. Keck CM, Muller RH. Drug nanocrystals of poorly soluble drugs produced by high pressure
homogenization. Eur J Pharm Biopharm 2006;62:3-16.
2. Mohamed AE, Viviane FN. Thermodynamics of paracetamol solubility in sugar-water cosolvent
systems. Int J Pharm 1990;58:177-84.
3. Yalkowsky SH, Rubino JT. Solubilization by cosolvents I: organic solutes in propylene glycol-water
mixtures. J Pharm Sci 1985;74:416-21.
4. Ran Y, Jain A, Yalkowsky SH. Solubilization and preformulation studies on PG-300995 (An antiHIV drug). J Pharm Sci 2005;94:297-303.
5. www.medicines.com ,10-10-2007
6. Martin A, Bustamante P, Chun AHC. Physical Pharmacy. 4th ed. New Delhi: B.I. Waverly Pvt.
Ltd;1997.
7. Subrahmanyam CVS, Sreenivasareddy M, Venkatrao J, Gundurao P. Irregular solution behaviour
of paracetamol in binary solvents. Int J Pharm 1992;78:16-24.
8. Subrahmanyam CVS, Sarasija S. Solubility behavour of carbamazepine in binary solvents: Extended
Hildebrand solubility approach to obtain solubility and other parameters. Pharmazie 1997;52:93942.
9. Yalkowsky SH, Joseph TR. Solubilization by co-solvents I: organic solutes in propylene glycolwater mixtures. J Pharm Sci 1985;74(4):416-21.
10. 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.
11. 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.
12. Satheshbabu PR, Subrahmanyam CVS, Thimmasetty J, Manavalan R, Valliappan K. Solubility of
meloxicam in mixed solvent systems. Ethiop Pharm J 2007;25:23-8.
13. Seedher N, Bhatia S. Solubility enhancement of cox-2 inhibitors using various solvent systems.
AAPS Pharm Sci Tech 2003;4(3):1-9.
14. Subrahmanyam CVS. Essentials of physical pharmacy. 1st ed. Delhi: Vallabh Prakasan;2003.
15. Satheshbabu PR, Subrahmanyam CVS, Thimmasetty J, Manavalan R, Valliappan K. Extended
Hansen’s solubility approach: Meloxicam in individual solvents. Pak J Pharm Sci 2007;20(4):311-6.
16. Hoy KC. New values of the solubility parameters from vapour pressure data. J Paint Technol
1970;41:76-118.
17. Fedors RF. A method of estimating both solubility parameters and molar volumes of liquids. Polym
Eng Sci 1974;14:147-54.