Meena Kharwade et al.

/ Journal of Pharmacy Research 2012,5(8),4204-4206

Research Article Available online through
ISSN: 0974-6943 http://jprsolutions.info
Cosolvency – An Approach for the Solubility Enhancement of Lornoxicam
Meena Kharwade*, Mahitha. K, Subrahmanyam C.V.S., P.R. Sathesh Babu
Gokaraju Rangaraju College of pharmacy, Osmania University, Hyderabad.
*Jawaharlal Nehru Technological University, Hyderabad, Andhra Pradesh, India.
Received on:12-05-2012; Revised on: 17-06-2012; Accepted on:28-07-2012

ABSTRACT
Solubility of lornoxicam in various pure solvents and solvent-cosolvent mixtures was studied to understand drug vehicle interactions and in order to get
the required solubility equal to the dose of lornoxicam, i.e., 4 mg/ml for development of solution formulation. Polyethylene glycol (PEG) 400, propylene
glycol, ethanol, water, dimethyl formamide, dimethyl sulfoxide, and ethyl acetate were used as solvents and propylene glycol-water, PEG 400-water,
PEG 400-propylene glycol, PEG 400-ethanol were used as solvent mixtures. Solubility of lornoxicam was low in water, but increased drastically when
semi-polar solvents were added. In PEG 400, dimethyl formamide, dimethyl sulfoxide solubility of lornoxicam was greater than 4.0 mg/ml. The increase
in the volume fraction of cosolvent resulted in an increase in solubility of lornoxicam. Based on the solubilization powers, which was determined from
slope of their log solubility vs cosolvent volume fraction plots, PEG 400 was found to be a better cosolvent. PEG 400 with the large nonpolar parts and
several hydroxyl groups were responsible for enhancing the solubility. The blend of ethanol and PEG 400 provided matching polarity for enhanced
solubility of lornoxicam. PEG 400 and ethanol in the ratio of 7:3, 8:2, 9:1 were recommended for achieving minimum required solubility (4.0 mg/ml) and
development of the lornoxicam solution formulation.

Key words: Solubilization, lornoxicam, solubility enhancement, cosolvency.

INTRODUCTION
As the structural complexity of new compounds increases, typically organic solvent that is used to increase the solubility or to increase the
solubility of the molecule is reduced dramatically. When the aqueous chemical stability. Cosolvent solubilization is particularly important for
solubility of a drug is well below its therapeutic dose, a mixture of solvents parenteral dosage forms, where it is desirable to incorporate the required
is added to achieve sufficiently high solubility. Cosolvents can increase the dose as a true solution in smallest volume of liquid as possible 10,11.
solubility of a nonpolar drug up to several orders of magnitude compared to
its aqueous solubility. This is essential for a formulation where it may be Lornoxicam is a new nonsteroidal antiinflammatory drug, a thienothiazine
necessary to increase substantially the solubility of a drug1. Other methods derivative of “oxicam” class of NSAIDs and has both oral and injection
such as complexation or micellization may not achieve the desired solubility dosage forms for commercial use in the treatment of pain associated with a
for a therapeutic dosage. Techniques such as complexation could suffer, variety of conditions, including rheumatoid arthritis, osteoarthritis,
because identification of a suitable substance that will form a soluble complex ankylosing spondylitis and postoperative dental pain usually administered
with the drug may not be possible, unless the drug conforms to certain at a dose of 4 mg/ml12,13. The drug has poor water solubility and wettability,
structural requirements 2 . The use of surface-active agents in drug which produces difficulties in formulation and led to variable bioavailability.
formulations may result in toxicity problems, especially when given by the In this study, the effect of a cosolvent system to increase lornoxicam solubility
parenteral route3. Enhancement of solubility by decreasing the particle size was evaluated. The aim of study is to determine the solubility of lornoxicam
and increasing surface area is one of the mechanical approaches. Upon and to predict the efficiency of cosolvents on the solubilization of
decreasing the particle size, fine drug particle have tendency to agglomerate lornoxicam. Keeping in view of the dose of lornoxicam i.e. 4 mg/ml 12,13, the
due to Van der Waal’s forces of attraction or hydrophobicity, which result work is significant in relation to the development of parenteral formulation
in decrease in surface area4,5. Even though methods such as prodrug and salt of lornoxicam. More emphasis is given on the PEG 400 as a cosolvent and
formation can result in increased solubility, it requires synthesis of new other vehicles as a solvents.
drug entities that results in additional animal studies to confirm their efficacy
and toxicity6. Thus, the advantage of using cosolvents is a simple approach, MATERIALS AND METHODS
if dramatic increase in drug solubility is achieved and inexpensive, no need
for other expensive pharmaceutical technology for producing the dosage Materials
form7. The lornoxicam was a gift sample (Hetero drugs, Hyderabad, India). All
solvents used in the study were of analytical reagent grade (S.D. Fine-
Weak electrolytes and nonpolar molecules have poor water solubility and it Chem. Ltd., Mumbai) and double distilled water prepared in laboratory (all
can be improved by altering polarity of the solvent. Cosolvent system glass distillation apparatus). Absorption spectrum of lornoxicam in 0.05 N
works by reducing the interfacial tension between the aqueous solution and NaOH solution was taken in the range of 200 - 400 nm. Absorption maximum
hydrophobic solute (solvent blending) 8,9. A cosolvent is a water-miscible was obtained at 376 nm. Calibration curve was constructed and obeyed
Beer Lambert’s law in the range of 2.5 to 25 µg/ml.
*Corresponding author.
Mrs. Meena Kharwade Method
Assistant Professor, Determination of solubility
Gokaraju Rangaraju College of Pharmacy, The solubility of lornoxicam was determined by preparing saturated
Bachupally, Miyapur solutions in solvent and/or solvent blends14, 15. An excess of lornoxicam was
Hyderabad- 500090.
Andhra Pradesh, India added to an ampoule containing 5 ml of solvent or solvent blend. Ampoules

Journal of Pharmacy Research Vol.5 Issue 8.August 2012 4204-4206

 Meena Kharwade et al. / Journal of Pharmacy Research 2012,5(8),4204-4206
were shaken (number of revolutions is 100 per minute) in orbital shaker at
25 ± 1 °C for 24 hrs. The equilibrated solutions were then removed, filtered
(using whattman filters) to separate from the saturated solutions excess
undissolved drug. The saturated solutions were suitably diluted with 0.05
N sodium hydroxide solution and the concentration of lornoxicam was
determined spectrophotometrically16. Solubility experiments were conducted
in triplicate.
Theoretical solubility model for binary mixed-solvent system
A cosolvent system is a mixture of miscible solvents, which is often used to
dissolve water-insoluble drugs. Several investigators have developed
predictive model for cosolvent solubilization. A simple and accurate model
suitable for preformulation and requires little or no experimental data, is the
log-linear model7,11,17,18. It predicts a log linear increase in solubility with
increasing cosolvent as illustrated in Eq.(1)
log Smix = f ’ log Sc + (1- f ’) log Sw
Considering cosolvent C and solvent B, the general formula is:
log Smix = f ’log Sc + (1-f’’) log SB
where, Smix, Sc and Sw, SB are the solubilities of drug in solvent mixture,
cosolvent and water, solvent respectively.1- f’ and f’’ are the volume frac-
tion of the water or solvent and cosolvent in solvent blend.
The log-linear model can express the solubilization by cosolvent as given
below:
log Smix = f log SB + f’σ
f is the volume fraction of the solvent in solvent blend and σ is the
solubilization power of cosolvent.
In a given cosolvent – water system, σ will be a constant. Therefore, if one
plots log Smix versus f’, the slope will be σ . Comparing slopes for different
cosolvent–water systems can easily be done by using σ , as a measure of the
solubilization potential of given cosolvent.
with decreasing solvent polarity. High values of octanol-water partition
coefficients of lornoxicam (log P = 3.15) suggested good solubility in lipo-
philic solvents. Ethanol was observed to be better solvent than water. In
propylene glycol, lornoxicam solubility was found to be 0.1540 mg/ml,
greater than water, probably through hydrogen bonding. Lornoxicam solu-
bility was 134 times higher in PEG 400 than water. PEG 400 with large
nonpolar part and several hydroxyl groups was responsible for the en-
hanced solubility. Other nonpolar solvents were also better than water,
DMSO and DMF showed 170 and 103 folds higher solubility respectively
as compared to water. Thus, propylene glycol, polyethylene glycol 400
and ethanol could be better cosolvents in case of lornoxicam. The solubility
behaviour of lornoxicam was extended to solvent blends of graded variation
of composition of cosolvents and solvent.
Solubility in binary cosolvent blend
The mixed solvent systems, namely PEG 400–water, propylene glycol–
water, PEG 400–propylene glycol and PEG 400–ethanol were used for
(1)
studying lornoxicam solubility.
In propylene glycol–water system, as the volume fraction of propylene
glycol (cosolvent) increased, solubility of lornoxicam increased. This might
(2)
be because of propylene glycol could reduce water’s ability to squeeze out,
hydrophobic compound by disrupting water self-association. But this en-
hancement fails to achieve the desired solubility for lornoxicam (4 mg/ml).
The solubility of lornoxicam in mg/ml were plotted against the volume
fraction, f’, of cosolvent system, i.e., PEG 400–water, PEG 400–propy-
lene glycol, PEG 400–ethanol (Figure 1).
As the volume fraction of cosolvent (PEG 400) increased, the solubility
(3) was increased (Figure 1). Solubility of lornoxicam was increased both in
other systems too (PEG 400-water and PEG 400-propylene glycol sys-
tems). The minimum required solubility was not obtained in both the sys-
tems. PEG400-propylene glycol showed higher solubility than the PEG
400-water system, when volume fraction (f’) of PEG 400 was less than 0.7,
beyond f’= 0.8, the solubility was significantly increased (Figure 1). The
intermolecular interactions between PEG 400 and propylene glycol must
be facilitating the solubility at higher volume fraction and thus squeezing
out the lornoxicam was reduced drastically.

RESULTS AND DISCUSSION
Solubility in pure solvents
The solubility enhancement factor was calculated from the ratio of lornoxicam
solubility in 1 ml of the selected solvent or solvent blend to 1 ml of water.
The solubility of lornoxicam in different solvents at 25°C was studied and
solubility data were given in Table 1. The enhancement factor varied and the
maximum observed was 170. As the polarity of solvent decreased, the
enhancement factor was increased.
In PEG 400-ethanol system, at higher fractions of PEG 400, the required
solubility was obtained. The PEG 400-ethanol system showed higher solu-
bility compared to other systems at all volume fractions (f’), of polyethyl-
ene glycol 400. The f’ values are 0.9, 0.8, 0.7 and the respective solubilities
were 5.60 mg/ml, 4.85 mg/ml and 4.13 mg/ml. These systems satisfied the
minimum required solubility. Ethanol could be better solvent. The blend of
ethanol and PEG400 might provide matching polarity to enhance solubility
8
7

The lornoxicam exhibited poor solubility in water (Table1), being predomi-

6
nately nonpolar and water cannot effectively break into lattice structure of Dose of lornoxicam in
Solubility of lornoxicam

lornoxicam. The solubility of lornoxicam in other solvents was increased injection (4 mg/ml).
5
(mg/ml)

Table 1. Lornoxicam solubility and enhancement factor in various 4

solvents at 25° C.
3 PEG 400-water
Solvent Concentrationa Enhancement factorb
AM ± SD, (mg/ml) PEG 400-Propylene glycol
2
Water 0.0535 ± 0.0151 1 PEG 400-Ethanol
Ethanol 0.0843 ± 0.0156 2 1
Propylene glycol 0.1540 ± 0.0370 3
Ethyl acetate 0.4138 ± 0.0221 8
DMF 5.5284 ± 1.1410 103 0
PEG 400 7.1758 ± 1.2634 134 0 0.2 0.4 0.6 0.8 1 1.2
DMSO 9.0896 ± 2.0977 170
'
a
Volume fraction, f
Three determinations (n=3).
b
Is calculated by the ratio of lornoxicam solubility in 1 ml of solvent/1 ml of Fig. 1: Relationship between volume fraction of various cosolvent systems
water, at 25°C. and solubility of lornoxicam.
Journal of Pharmacy Research Vol.5 Issue 8.August 2012 4204-4206
 Meena Kharwade et al. / Journal of Pharmacy Research 2012,5(8),4204-4206
Table 2. Relationship between logarithmmic theoretical and experimental lornoxicam solubility in various solvent-cosolvent blends at 25°C.
PEG400 cosolvent Solvent PG Water Ethanol
(volume (volume log Smix log Smix Enhancement log Smix log Smix Enhancement log Smix log Smix Enhancement
fraction) fraction) expt theoratical factor expt theoratical factor expt theoratical factor

0 1 -0.81 -0.81 2 -1.27 -1.27 1 -1.07 -1.07 2

0.1 0.9 -0.16 -0.65 13 - - -0.02 -0.88 18
0.2 0.8 -0.07 -0.48 16 - - 0.048 -0.69 21
0.3 0.7 -0.03 -0.31 18 - - 0.085 -0.5 23
0.4 0.6 -0.03 -0.15 18 - - 0.123 -0.1 25
0.5 0.5 0.121 0.022 25 - - 0.146 -0.11 26
0.6 0.4 0.131 0.189 26 -0.18 0.005 13 -0.03 0.084 17
0.7 0.3 0.101 0.355 24 -0.27 0.217 11 0.616 0.277 77
0.8 0.2 0.22 0.522 31 0.267 0.43 35 0.686 0.472 91
0.9 0.1 0.269 0.689 35 0.3 0.643 38 0.704 0.663 95
1 0 0.856 0.856 134 0.856 0.856 134 0.856 0.856 134
Cosolvent
solubilization
power σ - 1.167 2.322 1.93

of lornoxicam and can be a good cosolvent system for the development of
the lornoxicam parenteral formulation.
In theoretical modeling of solubility of lornoxicam in binary mixtures, solu-
bility (molar concentration) was expressed in logarithmic scale. The experi-
mental and theoretical solubility data for PEG 400-water, propylene gly-
col-water, PEG 400-propylene glycol, PEG 400-ethanol were shown in
Table 2. For all PEG 400 based cosolvent systems, good correlation was
observed between f’ and log Smix i.e., as f’ was increased the solubility of
lornoxicam was increased in binary systems.
The σ was obtained as a slope from the linear graph of theoretical log Smix
versus volume fraction of cosolvent (f’). The data were given in the Table 2.
For a cosolvent system, the solubilization power (s) gave a quantitative
estimate of the ability of a cosolvent to increase the solubility of the drug in
a given solvent13. Lower the cosolvent’s solubilization power, the weaker
the cosolvents. Hence propylene glycol is not a good cosolvent (σ = 0.459)
for lornoxicam. PEG 400 exhibited good solubilization power irrespective
of the other solvent used (water, propylene glycol or ethanol). The solubi-
lization power was correlated with cosolvent polarity, greater the differ-
ence in the polarity of two solvents, greater is the power of solubilization.
Though the solubilization power of PEG 400–water blend was more (σ =
2.322) as compared to PEG 400–PG and PEG 400–ethanol, yet the solubil-
ity of lornoxicam in PEG 400–water blend was less than clinically recom-
mended dose. Lornoxicam solubility equal to or more than 4 mg/ml was
observed in PEG 400-ethanol mixture in which the solubilization power of
PEG 400 is good ( σ = 1.93) as compared to PEG 400-PG system.
CONCLUSIONS
The solubility of lornoxicam was higher in PEG 400 and DMSO, i.e., 7.1
and 9.0 mg/ml respectively. The solubility of lornoxicam was enhanced
successfully in cosolvent systems (PG–water, PEG 400-water, PEG 400-
ethanol, PEG400-PG). Based on the solubilization power (σ), PEG 400
was observed to be a better cosolvent as compared to PG. Greater the
difference in the polarity of two solvents, greater is the power of solubili-
zation. This is in tune with the results obtained, as the difference in the
polarity between PEG 400-water (σ = 2.322) was higher as compared to
PEG 400-PG (σ = 1.167). In general the above systems were good solvent
blend for lornoxicam, but the minimum required solubility is achieved in
PEG 400-ethanol blend at a volume fraction of 0.7 and more. Though
ethanol was not a good solvent individually, PEG 400–ethanol (σ = 1.93)
blend was suitable for enhancing the solubility of lornoxicam. These stud-
ies, concluded that combination of PEG 400-ethanol, as a vehicle for use in
the liquids requiring a dose of 4 mg/ml.
REFERENCES
1. Rong Liu, Water insoluble drug formulation, 2 nd Ed. New Jersey,
USA, CRC press, 2008.
Source of support: Nil, Conflict of interest: None Declared
Journal of Pharmacy Research Vol.5 Issue 8.August 2012
2. Tugba GR, Neslihan G, Levent, Nanocrystal Technology for Oral
Delivery of Poorly Water-Soluble Drugs, Journal of Pharmaceutical
Sciences, 2009, 55,34, 55-65.
3. Attwood D, Florence AT, The Surfactant systems: their chemistry,
pharmacy and biology, New York, USA, Chapman & Hall, 1983.
4. Lin SL, Menig J, Lachman L, Interdependence of Physiological
Surfactant & Drug Particle Size on the Dissolution Behavior of
Insoluble Drugs, Journal of Pharmaceutical Sciences, 1968, 7,2143-
2146.
5. Rasenack N, Hartenhauer H, Mullar BW, Microcrystal for
Dissolution Enhancement of Poorly Soluble Drugs, International
Journal of Pharmaceutics, 2003, 254,137-145.
6. Kawakami K, Oda N, Miyoshi K, Funaki T, Ida, Solubilization
Behavior of a Poorly Soluble Drug under Combined Use of
Surfactants and Cosolvents, European Journal Pharmaceutical
Sciences, 2006, 28(1-2),7-14.
7. Yalkowsky SH, Roseman TJ, Techniques of solubilization of
drugs, New York, USA, Marcel Dekker Inc, 1981.
8. Pinnamaneni S, Das NG, Das SK, Formulation Approaches for
Orally Administered Poorly Soluble Drugs, Pharmazie, 2002,
57,291-300.
9. Krishna G, Chen KJ, Lin CC, Nomeir AA, Permeability of Lipo-
philic Compounds in Drug Discovery using in-vitro Human Ab-
sorption Model Caco-2, International Journal of Pharmaceutics,
2001, 222,77–89.
10. Nema S, Washkuhn RJ, Brendel RJ, Excipients and their Use in
Injectable Products, Journal of Pharmaceutical Sciences &
Technology, 1997, 51,166–171.
11. Strickley RG, Solubilizing Excipients in Oral and Injectable For-
mulations, Pharm. Res. 2004, 21, 201-230.
12. http://cool.conservation-us.org/coolaic/sg/bpg/annual/v3-04.html.
13. http://www.labseekar.com/chemical biotech/chem.-more info.asp.
14. Subrahmanyam CVS, Sreenivasa Reddy M, Venkata Rao J, Gundu
Rao P, Irregular Solution Behaviour of Paracetamol in Binary
Solvents, International Journal of Pharmaceutics, 1992, 78,17-
24.
15. Bustamante P, Pena MA, Barra J, Partial Solubility Parameters
of Piroxicam and Niflumic acid, International Journal of Pharma-
ceutics, 1998, 174,141-150.
16. Nemutlu E, Demircan S, Kir S, Determination of Lornoxicam in
Pharmaceutical Preparations by Zero and First Order Derivative
UV Spectrophotometric Methods, Pharmazie, 2005, 60(6) ,421-
425.
17. Yalkowsky SH, Rubino JT, Solubilization of Cosolvents:Organic
Solutes in Propylene Glycol-Water Mixtures, Journal of pharma-
ceutical Sciences, 1985,74,416-421.
18. Ming-Kung Yeh, Li-Chien Chang, Andy Hong-Jey Chiou, Im-
proving Tenoxicam Solubility and Bioavailability by Cosolvent
System, AAPS Pharm Sci Tech, 2009,10(1),167-168.
4204-4206