Enhancement of Solubility of Poorly Water Soluble Drugs Diclofenac
Sodium by Mixed Solvency Approach
Masheer Ahmed Khan*
School of
Pharmacy, Devi Ahilya Vishwavidyalaya,
Takshshila Campus, Khandwa
Road, Indore-452001, India
ABSTRACT:
Enhancement of solubility is one of the
difficult tasks which become challenges in formulation development of orally
administered drug with poor aqueous solubility. Poor water solubility of drugs
often causes significant problems in producing formulations of sufficiently high
bioavailability, preventing effective use of the drugs. 'Mixed-solvency '
concept is the phenomenon to increase the solubility of poorly water-soluble
drugs in the aqueous solution containing blends of hydrotropic agents,
co-solvents and water soluble solutes which may give synergistic enhancement
effect on solubility of such drugs. In
the present investigation , mixed solvency approach has been applied for the
enhancement of aqueous solubility of a poorly water- soluble drugs diclofenec sodium
(selected as a model drug), by making blends of randomly selected water-soluble
substances from among the hydrotropic (urea, sodium acetate); water soluble
solutes (PEG4000, PEG6000); and co-solvents (PEG200, PEG400). The aqueous
solubility of diclofenac sodium was observed at room
temperature in the randomly selected
blends of solubilizers containing different
combinations keeping total concentration 50%w/v constant. Diclofenec
sodium have λmax 276 nm and obeys Beers Law in
concentration range of 10-60 µg/ml. The results suggest that solubility of the diclofenac sodium containing blends of varying combinations
was enhanced significantly using mixed solvency approach.
KEYWORDS: solubility, mixed-solvency
INTRODUCTION:
Solubility enhancement is one of the
important parameters which should be considered in formulation development of
orally administered drug with poor aqueous solubility. Solubility is defined in
quantitative terms as the concentration of the solute in a saturated solution
at a certain temperature and in qualitative terms, it may be defined as the
spontaneous interaction of two or more substances to form a homogenous
molecular dispersion. The saturated solution is the one in which the solute is
in equilibrium with the solvent. The solubility of a drug may be expressed as
parts, percentage, molarity, molality,
volume fraction and mole fraction. Some authors presented detailed review on
different drug solubilization techniques. They are pH
adjustment, micronization, micellar
solubilization, co solvency and salting in, hydrotropy etc. Maheshwari,
has proposed the concept of mixed solvency. The author is of the opinion that
all substances have solubilizing power and all
soluble substances whether liquids, solids, or gases may enhance the aqueous
solubility of poor water-soluble drugs.
Solubility studies were carried in the solutions
containing hydrotropic agents (urea and sodium acetate ), co solvents (PEG200
and PEG 400) and water soluble solids (PEG 4000 and PEG 6000) in randomly prepared blends keeping total
concentration constant i.e. 50% w/v. Results shows synergistic effect on
solubility enhancement of the drug substance [1-11].
MATERIALS UNDER METHODS:
Gift sample of drug Diclofenac sodium was
procured from M/s Aerrow Pharmaceuticals, Indore,
M.P. All the chemicals and solvents used
were of analytical grade. Purified water was used to prepare the solutions of solubilizers. A spectrophotometer (UV-1700 Shimadzo) was used for quantitative analysis.
Methods
Diclofenac sodium (40 mg) was accurately
weighed and transferred to 50 ml volumetric flask. To this 40 ml of distilled
water was added. The flask was shaken to dissolve the drug and volume was made
up to the mark with distilled water. The stock solution was further diluted
with distilled water to obtain various dilutions containing between 10-60
µg/ml. Absorbance was noted at 276nm
against reagent blanks to get the calibration curve. The Solubility of diclofenec sodium in distilled water was observed and shown
in Table (1).
Table (1):
Solubility of diclofenac sodium in purified water
|
S. No. |
Concentration |
Absorbance |
|
1 |
10µg/ml |
0.21 |
|
2 |
20µg/ml |
0.42 |
|
3 |
30µg/ml |
0.64 |
|
4 |
40µg/ml |
0.76 |
|
5 |
60 µg/ml |
0.92 |
Blends (50%w/v constant) of solubilizers were prepared by using varying concentrations
of the solvents. Blend-1 containing urea, PEG4004, PEG400 and Sodium acetate,
Blend- 2 contains urea, PEG6000, PEG200 and Sodium acetate, Blend -3 contains
urea, PEG200, PEG400 and Sodium acetate and Blend- 4 contains urea, PEG400,
PEG6000 and Sodium acetate as shown in Table (2). Bulk drug was first dissolved
in 10ml of blend 1.The solution was vigorously shaken for a definite time with
regular intervals until a supersaturated solution is obtained. The resulting
solution was diluted up to 1000ml with the blend. Absorbance of this solution
was noted at 276nm against the solvent blend. The same procedure was followed
with the other blends i.e. blend2, blend3 and blend4 respectively and
absorbance were noted at the same wavelength. The corresponding concentration
gives the solubility of the drug and thus the enhanced solubility of the drug
was calculated by comparing the solubility of the drug in water.
RESULTS AND DISCUSSION:
The results obtained are shown in Table (3)
for the solubility of diclofenac sodium in different
blends. From the table it is evident that there was improvement in the
solubility of diclofenac sodium in blend (50% w/v)
containing urea, PEG-200, PEG-400, PEG-4000, PEG-6000 and sodium acetate in
varying concentrations. On comparing Table(2) and Table(3) the drug solubility was found to be enhanced
by 2.31, 3.58, 3.80 and 3.90 folds with blend-1, blend-2, blend 3 and blend 4
respectively. The greatest enhancement in solubility was observed in the
Blend-4 and least in case of Blend-1.These results demonstrate the principle of
mixed-solvency concept that water soluble substances whether hydrotropic or
solvents or water-soluble solids can be combined randomly in varying concentrations
and gives enhanced solubility to poorly water-soluble drugs. Blends of water
soluble substances can be prepared in safe level of concentrations of
individual solubilizers to give a concentrated
solution to act as solubilizing system for development
of their different dosage forms.
CONCLUSION:
The solubility of the diclofenac
sodium containing different combinations of urea, PEG-200, PEG-400, PEG-4000,
PEG-6000 and sodium acetate in varying concentrations was enhanced
significantly, using this mixed-solvency approach. Therefore the results
suggest that mixed –solvency approach can also be used successfully for the
enhancement of solubility of other poor water-soluble drugs.
Table (2): Contents of Blends
|
BLEND-1 |
BLEND-2 |
BLEND-3 |
BLEND-4 |
||||
|
HYDROTROPE |
% |
HYDROTROPE |
% |
HYDROTROPE |
% |
HYDROTROPE |
% |
|
Urea |
10% |
Urea |
10% |
Urea |
15% |
Urea |
15% |
|
PEG-4000 |
10% |
PEG-6000 |
10% |
PEG-200 |
10% |
PEG-400 |
15% |
|
PEG-400 |
15% |
PEG-200 |
15% |
PEG-400 |
15% |
PEG-6000 |
10% |
|
Sodium acetate |
10% |
Sodium acetate |
15% |
Sodium acetate |
10% |
Sodium acetate |
10% |
Table (3):
Solubility of diclofenac sodium in different blends
|
S. No. |
Blend No. |
Absorbance |
Saturated Solubility |
|
1 |
Blend-1 |
1.152 |
139µg/ml |
|
2 |
Blend-2 |
1.780 |
215
µg/ml |
|
3 |
Blend-3 |
1.890 |
228
µg/ml |
|
4 |
Blend-4 |
1.932 |
234 µg/ml |
ACKNOWLEDGEMENT:
The author is thankful to M/s Aerrow Pharmaceuticals, Indore, M.P., for providing gift
sample of drug for the studies.
REFERENCES:
1.
Masheer Ahmed
Khan ,Anand Chourasia ,
Mixed solvency approach- Boon for solubilization of
poorly water soluble drug diclofenac sodium, Research
Journal of Pharmaceutical, Biological and Chemical Sciences, 2012,vol3,Issue4,
865-868.
2.
Masheer Ahmed
Khan ,Novel application of Mixed solvency concept using poorly water soluble
drug diclofenac sodium, International Journal of
research in Pharmacy and Chemistry, 2012,2(4), 1040-1042.
3.
Maheshwari, RK., Solubilization of ibuprofen by mixed solvency approach, The
Indian Pharmacist, 2009, vol VIII,No.87;81-83.
4.
Maheshwari RK, Deswal S, Aher R, Wanare G, Jawade S, Indurkhya A, Jagwani. Ibuprofen
Sodium: A Novel Hydrotropic Agent for estimation of poorly water-soluble drugs,
Journal of Applied Chemical Research,
2009; 10: 56-60.
5.
Maheshwari RK, Chavada V, Shahoo K, and Varghese
S., Analysis of bulk sample of salicylic acid by application of hydrotropic solubilization method, Indian journal of pharmaceutical
science 2008; 70(6): 823-825.
6.
Maheshwari RK, Deswal S, Tiwari D, Ali N, Pothen B, Jain S. Novel spectrophotometric estimation of frusemide using hydrotropic solubilization
phenomenon, Indian Journal of
Pharmaceutical Science 2007; 69(6): 822-824.
7.
Maheshwari, RK., Chaturvedi,SC.,and Jain,NK.,
Application of hydrotropy in spectrophotometric
determination of pharmaceutical dosage forms, Indian drugs, 42; 2005,760-763.
8.
Maheshwari RK, Chavada V, Shahoo K, and Varghese
S.,Novel application of hydrotropic solubilization in the spectrophotmetric
analysis of diclofenec sodium in solid dosage forms,
Asian Journal of Pharmaceutics; 2006, volume1, Issue1, 30-33.
9.
Indian Pharmacopoeia, Controller of
Publications, Delhi, 1996, Vol1, 388.
10.
Etman,MA and
Nada, AH., Hydrotropic and cosolvent solubilization of indomethacin, Acta Pharma., 49,1999,291-298.
11.
Patel R, Patel N, Patel N M, Patel M ., A
novel approach for dissolution enhancement of Ibuprofen by preparing floating
granules, Int. J. Res. Pharm. Sci. Vol-1, Issue-1, 57-64, 2010.
Received on 03.12.2012
Modified on 16.12.2012
Accepted on 31.12.2012
© A&V Publication all right reserved
Research Journal of Pharmaceutical Dosage Forms and Technology.
4(6): November–December, 2012, 39-41