Pharmaceutical Development and Technology, 2009; 14(2): 185–192

R e s e a R c h a R t i c l e

Co-solvent solubilization of some poorly-soluble antidiabetic drugs

Neelam Seedher, and Mamta Kanojia

Department of Chemistry, Panjab University, Chandigarh, India

Address for Correspondence: Prof. Neelam Seedher, PhD, Department of Chemistry, Panjab University, Chandigarh, 160014 India; E-mail: nseedher@yahoo.com

(Received 18 June 2008; revised 12 August 2008; accepted 16 August 2008)

Introduction

The antidiabetic drugs used in the present work belong to class II (poor solubility and high permeability) of the biopharmaceutical classification system (BCS). Poor aqueous solubility not only gives rise to difficulties in the design of pharmaceutical formulations and leads to variable oral bioavailability, it also limits the pharma-ceutical development of a drug since a solution of drug is usually required to perform various pharmacological, toxicological and pharmacokinetic studies.[1,2] Most of the reported work on solubility enhancement of antidiabetic drugs involves preparation of solid dispersions,[3,4] use of surfactants,[5,6] and complexation with cyclodextrins.[7–9] However, a large increase in solubility can be achieved by the use of co-solvents. Co-solvent solubilization is a simple and effective technique, widely used to enhance the solubility of poorly soluble drugs.[10–12] In the present work, an attempt has been made to enhance the solu-bility of seven antidiabetic drugs; gliclazide, glybu-ride, glipizide, glimepiride, repaglinide, pioglitazone

hydrochloride and rosiglitazone maleate by pH modifi-cation and use of solubilizing co-solvents.

Materials and methods

Drugs used were obtained as gift from various manufac-turers. The purity of drug samples was more than 99%. All other reagents were of analytical grade. Water used was double distilled in an all glass apparatus.

Drug analysis

Drug estimation was done using ultraviolet absorption spectroscopic technique. Standard drug solutions in the appropriate solvent were prepared in the concentration range 10–100 M and the ultraviolet absorption spectra were measured against solvent blank. Extinction coef-ficients in the relevant solvent, determined from the absorbance at wavelength corresponding to absorption maxima (

max) versus drug concentration plots, were

ISSN 1083-7450 print/ISSN 1097-9867 online © 2009 Informa UK LtdDOI: 10.1080/10837450802498894

abstractCo-solvent solubilization approach has been used to enhance the solubility of seven antidiabetic drugs: gliclazide, glyburide, glipizide, glimepiride, repaglinide, pioglitazone, and roziglitazone. Solubility in water, phosphate buffer (pH 7.4), six co-solvent solutions prepared in water as well as phosphate buffer (pH 7.4) and pH-solubility profile of various drugs have been determined at 25°C. Aqueous solubility of various drugs was found to be less than 0.04 mg/mL. Solubility of gliclazide, glipizide and repaglinide increased by 3-6 times by using phosphate buffer (pH 7.4) as solvent. Solubility enhancement by pH modification was not sufficient. Significant enhancement in solubility could be achieved by the use of co-solvents. The com-bined effect of co-solvent and buffer was synergistic and enormous increase in solubility of sulfonylureas and repaglinide could be achieved. In the case of glitazones, however, co-solvent alone caused significant enhancement; the presence of buffer had negative effect on the solubilization potential of the co-solvents. Up to 763, 316, 153, 524, 297, 792 and 513 times increase in solubility could be achieved in the case of gli-clazide, glyburide, glimepiride, glipizide, repaglinide, pioglitazone and rosiglitazone, respectively.

Keywords: Co-solvent; pH; solubility enhancement; antidiabetic drugs

http://www.informapharmascience.com/phd

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186 N. Seedher and M. Kanojia

used to calculate unknown drug concentrations using Beer lambert law. The solvents used for drug analysis were 0.1N NaOH in the case of sulfonylureas, 0.1N HCl in the case of glitazones and phosphate buffer (pH 7.4) in the case of repaglinide.

Solubility determination

For the determination of solubility, excess of drug was placed in contact with 5 mL of solvent in sealed coni-cal flasks. The flasks were maintained at 25°C and the contents were stirred on a magnetic stirrer for 24 h. Preliminary experiments showed that a time period of 24 h was sufficient for the attainment of equilibrium. The solution was centrifuged and the supernatant was filtered through 0.45 m filter. The absorbance of the clear solution was determined at

max of the drug after

suitable dilution with the appropriate solvent. Dilutions were done to ensure that the drug concentrations are within the Beer law limit. Co-solvents were included in the blank and the solvent used for dilution was the same as that used for making the samples. The concen-tration of drug was determined from Beer lambert law using extinction coefficients, determined in the relevant solvent. The solubility was calculated by multiplying the drug concentration, so obtained, by the appropri-ate dilution factor. The reported data are an average of three determinations. The relative standard deviations (RSD) in data were less than 10%. The following solvent/solvent-co-solvent systems were studied: water, 0.1M phosphate buffer (pH 7.4), 20 and 40% concentration of co-solvents: Polyethylene Glycol (PEG) 400, polyethyl-ene Glycol (PEG) 8000, propylene glycol (PG), glycerol, ethanol (EtOH) and PG + Ethanol (1:1). Co-solvent solu-tions were prepared in water as well as 0.1M phosphate buffer, pH 7.4 (PB). For determination of pH-solubility profile, 0.05M glycine-HCl/Glycine-NaOH buffers of different pH values were used.

Results and discussion

Structures of the antidiabetic drugs used in the present work are shown in Figure 1. Solubilities of the drugs in water at 25°C and the respective pK

a values are given

in Table 1. Aqueous solubility was found to be in the range 6–14 g/mL in the case of glyburide, glimepir-ide, glipizide and pioglitazone and 30–40 g/mL in the case of gliclazide, rosiglitazone and repaglinide. All the drugs could be categorized as poorly-soluble since the aqueous solubility was much smaller than that required corresponding to the minimum dose of these drugs. The studied drugs, being predominantly non-polar mol-ecules, cannot effectively break into the lattice structure of water and hence the water solubility is low. Solubility of various drugs in phosphate buffer (pH 7.4) at 25°C is also given in Table 1. Solubility of gliclazide, glipizide and repaglinide increased by 3–6 times (66–175 g/mL) by using phosphate buffer (pH 7.4) as solvent. In the case of glyburide and glimepiride, the increase was much smaller and pioglitazone and rosiglitazone, being hydrochloride and maleate salts, respectively, the per-centage ionization of drug decreases with increase in pH and therefore, solubilities in phosphate buffer were lower than that in water.

pH-Solubility Profile

The solubility data for various drugs in the pH range 2-10 is given in Tables 2a and 2b. Final pH values of the saturated drug solutions have been reported. All the drugs, except glipizide had some degree of amphoteric character since the solubility at the two extremes of pH scale was higher than the values in the middle of the pH range. pH-solubility profile of glipizide, reported by Jamzad and Fassihi,[13] also does not show amphoteric behaviour for this drug. Slightly lower solubilities at

Table 1. pKa values and solubilities of various drugs in water and

0.1M phosphate buffer (pH 7.4) at 25°C.

Drug

Solubility (g/mL) pK

a1

pK

a2Water Phosphate buffer*

Gliclazide 37.32 175.06 5.80 –

Glyburide 5.96 8.22 5.30 –

Glimepiride 6.40 8.63 6.30 –

Glipizide 10.23 66.48 5.90 –

Repaglinide 39.82 140.86 4.16 6.01

Pioglitazone 14.05 10.61 7.24 –

Rosiglitazone 30.67 3.79 6.10 6.80

*Phosphate buffer (pH 7.4).

Table 2(a). Solubility of sulfonylureas at different pH values.

Gliclazide Glyburide Glimepiride Glipizide

pH Solubility (g/mL) pH Solubility (g/mL) pH Solubility (g/mL) pH Solubility (g/mL)

2.67 71.55 2.12 6.54 2.03 10.80 2.69 2.99

3.69 32.57 3.24 3.26 2.93 7.61 3.62 3.28

4.47 33.84 4.39 2.46 4.00 2.39 4.03 2.26

5.73 68.88 6.98 2.70 6.88 13.71 6.72 9.48

8.24 785.65 8.31 42.00 8.40 46.70 8.20 232.73

9.74 1475.36 9.58 262.08 9.53 664.28 9.41 637.32

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Solubilization antidiabetic drugs 187

Figure 1. Structures of the antidiabetic drugs used.

Gliclazide:

N N

O

N

SO

O

Glibenclamide:

S

O

O

HN

HN

O

NH

O

OCH3

Cl

Glimepiride:

N

O

H2CH3C

H3C

C

NH

O

CH2

CH2

SO2

NH

C

O

NH

H

CH3

N

Glipizide:

N NS

NN

O

OO

O

H

Pioglitazone:

N

H3C

O N

S

OO

HCl.

.

Rosiglitazone:

N NO

CH3

SNH

O

O

COOH

COOH

Repaglinide:

N

NO

O

O

O

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188 N. Seedher and M. Kanojia

different pH values reported by them may be due to the difference in the drug-solvent contact time which was 24 h in our studies as compared to 15 hours in the Jamzad and Fassihi data. Amphoteric properties of repaglinide have also been reported by Mandic and Gabelica.[14] Due

to the marked delocalization of the nitrogen lone elec-tron pair by the sulfonyl group, sulfonylureas are known to behave as weakly acidic drugs with pK

a values in the

range 5.3–6.3 (Table 1).[15,16] Accordingly for these drugs, the solubility in the alkaline range was found to be much higher than that in the acidic range. Repaglinide and pioglitazone had about equal solubility at the two extremes of the pH scale while in the case of rosiglita-zone, the effect of pH on solubility was not very pro-nounced. pH-dependence of solubility in all cases could not be explained on the basis of ionization behaviour (pK

a values) of drugs. This is because in addition to ioni-

zation, drug lipophilicity, hydrogen bonding ability and intermolecular interactions between drug molecules are other important factors which govern the solubility of a drug. Since buffer components are also known to

Table 2(b). Solubility of repaglinide and glitazones at different pH values.

Repaglinide Pioglitazone Rosiglitazone

pH Solubility pH Solubility pH Solubility

1.84 521.52 1.83 52.60 1.55 61.49

3.37 29.38 2.57 38.63 2.51 54.84

3.84 17.49 3.92 4.55 3.57 46.32

6.76 13.84 7.39 6.35 4.79 45.76

9.13 337.63 8.82 19.19 7.85 54.68

10.01 507.63 9.52 49.96 9.65 55.26

Table 3. Solubility of sulfonylureas and repaglinide in the absence and presence of aqueous solutions of various co-solvents.

Drug/co-solvent

Solubility (g/mL)

Conc. of co-solvent in

Water Phosphate buffer (pH 7.4)

Gliclazide 0% 20% 40% 0% 20% 40%

PEG400 37.32 120.87 559.93 175.06 1723.80 10936.03

PEG8000 37.32 75.36 575.50 175.06 1629.79 28466.27

PG 37.32 98.16 268.74 175.06 7814.25 9595.65

Glycerol 37.32 60.01 267.11 175.06 1873.76 15032.08

Ethanol 37.32 82.95 512.05 175.06 973.98 15365.70

PG + EtOH 37.32 91.96 205.49 175.06 4024.15 19918.43

Glyburide 0% 20% 40% 0% 20% 40%

PEG400 5.96 1.08 5.42 8.22 26.14 336.34

PEG8000 5.96 7.23 58.76 8.22 27.86 194.83

PG 5.96 3.37 8.14 8.22 21.93 82.31

Glycerol 5.96 1.39 2.35 8.22 6.81 14.04

Ethanol 5.96 6.53 169.99 8.22 104.41 1884.08

PG + EtOH 5.96 1.67 31.01 8.22 21.96 272.59

Glimepiride 0% 20% 40% 0% 20% 40%

PEG400 6.40 7.29 14.52 8.63 43.99 300.90

PEG8000 6.40 18.18 936.16 8.63 80.17 240.89

PG 6.40 29.00 103.06 8.63 50.17 176.05

Glycerol 6.40 6.72 9.30 8.63 19.80 34.64

Ethanol 6.40 10.00 72.85 8.63 40.57 982.40

PG + EtOH 6.40 10.06 197.07 8.63 52.84 982.35

Glipizide 0% 20% 40% 0% 20% 40%

PEG400 10.23 15.14 22.25 66.48 236.02 2838.58

PEG8000 10.23 26.57 156.68 66.48 771.48 992.86

PG 10.23 20.40 21.39 66.48 518.20 1931.36

Glycerol 10.23 7.97 12.18 66.48 165.13 646.91

Ethanol 10.23 18.37 126.24 66.48 755.94 5363.38

PG + EtOH 10.23 30.40 34.65 66.486 733.08 2367.40

Repaglinide 0% 20% 40% 0% 20% 40%

PEG400 39.82 150.53 69.88 140.86 270.26 5948.75

PEG8000 39.82 156.02 176.49 140.86 1672.22 4220.96

PG 39.82 46.03 49.76 140.86 451.61 3618.55

Glycerol 39.82 46.60 46.21 140.86 259.31 546.94

Ethanol 39.82 40.15 171.34 140.86 511.86 10917.83

PG + EtOH 39.82 50.35 267.86 140.86 1042.71 11844.17

PG = Propylene glycol, PEG = Polyethylene glycol, EtOH = Ethanol, PG + EtOH (1:1).

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Solubilization antidiabetic drugs 189

solubilize drugs, solubility values reported in this sec-tion using glycine-NaOH buffer, did not match with the corresponding phosphate buffer (pH 7.4) solubilities in some cases. Such a buffer effect has also been reported by other workers.[17] Although solubility of these drugs could be enhanced by pH modification, the maximum solubility at the highest pH studied was much less than 1 mg/mL in all the cases except gliclazide. Solubility of gliclazide was about 1.5 mg/mL at pH 9.74. The pH-dependence of solubility can have useful applications in the design of formulations.

Co-solvent solubilization

Co-solvent addition is a highly effective technique for the enhancement of solubility of poorly soluble drugs.[10–12] The small non-polar hydrocarbon region in the co-solvent can reduce the ability of the aqueous sys-tem to squeeze out non-polar solutes by weakening the intermolecular hydrogen bonding network of water. The solubilization efficiency of a co-solvent depends upon the extent to which it weakens the structure of water.

The solubilities of various drugs (sulfonylureas, repa-glinide and glitazones) at 25°C in the absence and pres-ence of 20% and 40% aqueous solutions of various solu-bilizing co-solvents (PEG 400, PEG 8000, PG, Ethanol, Glycerol and 1:1 PG-Ethanol mixture) are given in Tables 3 and 4. Enhancement of solubility was observed in most cases. However, the efficacy of the solvent was found to vary with the nature of the drug. The extent of enhancement of aqueous solubility should be a function of the relative magnitudes of the solute-solvent and vari-ous inter- and intra-molecular solvent-solvent interac-tions, which in turn depend on the relative polarity and hydrogen-bonding ability of the solute and solvent. In

general, the extent of enhancement was much larger in the case of glitazones as compared to sulfonylureas and repaglinide. Amongst sulfonylureas enhancement was highest in the case of gliclazide and least in the case of glyburide. The decrease in the aqueous solubility of gly-buride in the presence of some of the co-solvents may be due to the salting out effect of the co-solvents.

Solubilization efficiency

Solubilization efficiency has been expressed in terms of solubility ratios, S

co-sol (w)/S

w, S

co-sol(b)/S

b, S

co-sol (b)/S

w and

Sco-sol (b)

/Sco-sol (w)

, where Sco-sol (w)

and Sw

are the solubility of drug in the presence and absence of co-solvent, respec-tively and S

co-sol (b) and S

b are the corresponding values

in buffer. The data is given in Tables 5 and 6. In the case of sulfonylureas and repaglinide, at 20% concentration of co-solvent in water, a 3–4.5 times enhancement in aqueous solubility was obtained and when the con-centration of the co-solvent was increased to 40%, the maximum solubility increase was about 7–146 times. Thus on increasing the concentration of the co-solvent from 20–40%, substantial increase in solubility was observed for various drugs. Although large solubility enhancement was observed, for these drugs the maxi-mum solubility was much less than l mg/mL, in most cases.

In the case of glitazones, the solubilization efficiency was found to be much higher, 52.4 times for pioglita-zone and 41.8 times for rosiglitazone at 20% co-solvent concentration. The corresponding increase in 40% co-solvent was 791.6 times for pioglitazone and 513.3 times for rosiglitazone. For these drugs, solubility greater than 1 mg/mL and 10 mg/mL could be attained at 20% and 40% concentration, respectively, of co-solvent in water.

Table 4. Solubility of glitazones in the absence and presence of aqueous solutions of various co-solvents.

Drug/co-solvent

Solubility(g/mL)

Conc. of co-solvent in

Water Phosphate buffer (pH 7.4)

Pioglitazone 0% 20% 40% 0% 20% 40%

PEG400 14.05 294.73 6508.51 10.61 19.12 20.00

PEG8000 14.05 78.45 10831.24 10.61 22.83 34.59

PG 14.05 154.93 11120.04 10.61 10.37 16.91

Glycerol 14.05 134.91 6802.45 10.61 25.00 36.78

Ethanol 14.05 244.45 5799.20 10.61 10.41 28.82

PG + EtOH 14.05 736.68 3210.63 10.61 47.46 245.38

Rosiglitazone 0% 20% 40% 0% 20% 40%

PEG400 30.67 114.70 5251.69 3.79 180.39 667.47

PEG8000 30.67 99.33 8415.25 3.79 192.05 308.04

PG 30.67 90.50 7645.83 3.79 42.99 60.88

Glycerol 30.67 87.27 15740.23 3.79 18.04 25.78

Ethanol 30.67 1282.79 12497.20 3.79 60.31 152.45

PG + EtOH 30.67 965.14 12895.08 3.79 74.06 790.34

PG = Propylene glycol, PEG = Polyethylene glycol, EtOH = Ethanol, PG + EtOH (1:1).

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190 N. Seedher and M. Kanojia

Combination: Co-solvent and Buffer

Since for all the drugs except glitazones, the solubil-ity in PB (pH 7.4) was higher than that in water, it was thought of interest to study the combined effect of co-solvent and buffer. For this purpose solubility was determined in the presence of 20 and 40% co-solvent solutions prepared in phosphate buffer (pH 7.4). Solubility in phosphate buffer (pH 7.4) in the absence and presence of 20 and 40% co-solvent solutions is given in Tables 3 and 4. The presence of co-solvent as well as buffer produced a very large increase in solubility in the case of sulfonylureas and repaglinide.

Enhancement of buffer solubility by co-solvents, expressed as ratio S

co-sol (b)/S

b, is given in Tables 5 and 6.

It is observed that the Sco-sol (b)

/Sb ratios are significantly

higher than the Sco-sol (w)

/Sw

ratios, indicating thereby that in buffer medium the enhancement caused by co-solvents is more as compared to the enhancement by co-solvents in water. The actual solubility enhance-ment is the enhancement of aqueous solubility by the combined effect of buffer and co-solvent and is given by S

co-sol (b)/S

w ratios in Tables 5 and 6. For sulfonylureas

and repaglinide, an enormous increase in solubility was observed. At 20% concentration of the co-solvent

Table 5. Solubilization efficiency of various co-solvents for sulfonylureas and repaglinide.

Drug/co-solvent

Solubility ratio

Concentration of co-solvent

Gliclazide 20% 40% 20% 40% 20% 40% 20% 40%

PEG400 3.2 15.0 9.9 62.5 46.2 293.0 14.3 19.5

PEG8000 2.0 15.4 9.3 162.6 43.7 762.7 21.6 49.5

PG 2.6 7.2 44.6 54.8 209.3 257.1 79.6 35.7

Glycerol 1.6 7.2 10.7 85.9 50.2 402.7 31.2 56.3

Ethanol 2.2 13.7 5.6 87.8 26.1 411.7 11.7 30.0

PG+EtOH 2.5 5.5 23.0 113.7 107.8 533.7 43.8 96.9

Glyburide 20% 40% 20% 40% 20% 40% 20% 40%

PEG400 0.2 0.9 3.2 40.9 4.4 56.5 20.6 62.0

PEG8000 1.2 9.9 3.4 23.7 4.7 32.7 3.9 3.3

PG 0.6 1.4 2.7 10.0 3.7 13.8 6.5 10.1

Glycerol .23 0.4 0.8 1.7 1.1 2.4 4.9 6.0

Ethanol 1.1 28.5 12.7 229.2 17.5 316.4 16.0 11.1

PG+EtOH 0.3 5.2 2.7 33.2 3.7 45.8 13.1 8.8

Glimepiride 20% 40% 20% 40% 20% 40% 20% 40%

PEG400 1.1 2.3 5.1 34.9 6.9 47.0 6.0 20.7

PEG8000 2.8 146.1 9.3 27.9 12.5 37.6 4.4 0.3

PG 4.5 16.1 5.8 20.4 7.8 27.5 1.7 1.7

Glycerol 1.1 1.5 2.3 4.0 3.1 5.4 3.0 3.7

Ethanol 1.6 11.4 4.7 113.8 6.3 153.3 4.1 13.5

PG+EtOH 1.6 30.8 6.1 113.8 8.3 153.4 5.3 5.0

Glipizide 20% 40% 20% 40% 20% 40% 20% 40%

PEG400 1.5 2.2 3.6 42.7 23.1 277.5 15.6 127.6

PEG8000 2.6 15.3 11.6 14.9 75.4 97.1 29.0 6.3

PG 2.0 2.1 7.8 29.1 50.7 188.8 25.4 90.3

Glycerol 0.8 1.2 2.5 9.7 16.2 63.3 20.7 53.1

Ethanol 1.8 12.3 11.4 80.7 73.9 524.4 41.2 42.5

PG+EtOH 3.0 3.4 11.0 35.6 71.7 231.5 24.1 68.3

Repaglinide 20% 40% 20% 40% 20% 40% 20% 40%

PEG400 3.8 1.8 1.9 42.2 6.8 149.4 1.8 85.1

PEG8000 3.9 4.4 11.9 30.0 42.0 106.0 10.7 23.9

PG 1.2 1.3 3.2 25.7 11.3 90.9 9.8 72.7

Glycerol 1.2 1.2 1.8 3.9 6.5 13.7 5.6 11.8

Ethanol 1.0 4.3 3.6 77.5 12.9 274.2 12.8 63.7

PG+EtOH 1.3 6.7 7.4 84.1 26.2 297.4 20.7 44.2

PG = Propylene glycol, PEG = Polyethylene glycol, EtOH = Ethanol, PG + EtOH (1:1); The highest solubilization achieved for each co-solvent at various concentrations is represented in italic.

S

Sco-sol(w)

w

S

Sco-sol(b)

b

S

Sco-sol(b)

w

S

Sco-sol(b)

co-sol(w)

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Solubilization antidiabetic drugs 191

in buffer, a 12- to 209-fold solubility enhancement could be observed as compared to 3–4.5 times for 20% co-solvent solutions in water. At 40% concentration of co-solvent, the increase was much larger, about 153–763 times as compared to 7–146 times for co-solvent solutions in water. S

co-sol (b)/S

co-sol (w) values in the

last two columns show that Sco-sol (b)

/Sw

ratios are much higher than the S

co-sol (w)/S

w ratios. Also data shows that

the Sb/S

w values, solubility ratios in the absence of

co-solvent, are much smaller than the Sco-sol (b)

/S co-sol(w)

values, in the presence of co-solvent. This shows that the significantly larger enhancement in the presence of co-solvent is not only due to higher pH of buffer. The presence of buffer and co-solvents has synergistic

effect. The efficiency of the co-solvents increases in the presence of buffer components. The only explanation which can be offered for the dramatic increase in the solubility when co-solvent solutions are prepared in buffer is given below.

The solubilization efficiency of a solvent is a func-tion of the relative magnitudes of the various solute-solute, solute-solvent and solvent-solvent interactions. Reduction in solute-solute and solvent-solvent interac-tions should increase the solubilization efficiency. The co-solvents used in the present work have a tendency to form inter- and intra-molecular hydrogen bonds. Higher pH of buffer and increase in the ionic strength due to the presence of buffer components should decrease

Table 6. Solubilization efficiency of various co-solvents for glitazones.

Drug/co-solvent

Solubility ratio

Concentration of co-solvent

Pioglitazone 20% 40% 20% 40% 20% 40% 20% 40%

PEG400 21.0 463.3 1.8 1.9 1.4 1.4 16.7 322.6

PEG8000 5.6 771.0 2.2 3.6 1.6 2.5 3.4 312.5

PG 11.0 791.6 2.2 1.6 1.6 1.2 6.7 666.7

Glycerol 9.6 484.2 1.0 3.7 0.7 2.8 12.5 172.4

Ethanol 17.4 412.8 2.4 2.7 1.8 2.1 10.0 200.0

PG+EtOH 52.4 228.6 1.0 23.1 0.7 17.5 100.0 13.1

Rosiglitazone 20% 40% 20% 40% 20% 40% 20% 40%

PEG400 3.7 171.2 47.6 176.0 5.9 21.8 0.6 7.9

PEG8000 3.2 274.4 50.6 81.2 6.3 10.0 0.5 27.3

PG 3.0 249.3 11.3 16.1 1.4 2.0 2.08 125.0

Glycerol 2.9 513.3 4.8 6.8 0.6 0.8 4.8 625.0

Ethanol 41.8 407.4 15.9 40.2 2.0 5.0 20.0 82.0

PG+EtOH 31.5 420.4 19.5 208.4 2.4 25.8 12.5 16.3

PG = Propylene glycol, PEG = Polyethylene glycol, EtOH = Ethanol, PG + EtOH (1:1); The highest solubilization achieved for each co-solvent at various concentrations is represented in italic.

Table 7. Solvents with drug solubility greater than that required for 5 mL dose.

Drug Common dose (mg)Required drug solubility for 5 mL

dose (mg/mL)Solvents with drug solubility greater than

that required for 5 mL dose

Gliclazide 80 16 40% PEG 8000 and PG + EtOH (20% each) in PB

Glyburide 5 1 40% EtOH in PB

Glimepiride 2 0.4 40% PEG 8000in water, 40% EtOH and PG + EtOH (20% each) in PB, pH 9.53

Glipizide 5 1 40% PEG 400, PG, EtOH and PG + EtOH (20% each) in PB

Repaglinide 1 0.2 PG + EtOH (20% each) in water, All solvents studied at 40% conc. in PB, pH 1.84, 9.13, 10.01

Pioglitazone 15 3 All solvents studied at 40% conc. in water,

Rosiglitazone 2 0.4 All solvents studied at 40% conc. in water, 20% EtOH and PG + EtOH (10% each) in water, 40% PEG 400, PEG 8000 and PG + EtOH (20% each) in PB

*PG = Propylene glycol, PEG = Polyethylene glycol, EtOH = Ethanol, PG + EtOH (1:1).

S

Sco-sol(b)

b

S

Sco-sol(b)

w

S

Sco-sol(w)

w

S

Sco-sol(w)

co-sol(b)

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192 N. Seedher and M. Kanojia

the ability of co-solvent molecules to form inter- and intra-molecular hydrogen bonds resulting in decrease in solvent-solvent interactions and consequent increase in solubility.

Solubility enhancement of glitazones by co-solvents in phosphate buffer medium have also been reported in Tables 4 and 6. The presence of co-solvents enhanced the buffer solubility of pioglitazone and rosiglitazone. However, the enhancement was found to be much less when the co-solvent solutions were prepared in phosphate buffer (pH 7.4) as compared to the values in aqueous solutions of co-solvents. The two glitazones, being hydrochloride and maleate salts, respectively, the percentage ionization of drug decreases with increase in pH and therefore, solubilities in phosphate buffer were lower than that in water. That might be the reason for the negative effect on the solubilization potential of the co-solvents in the presence of buffer. Since solubil-ity of glitazones is higher in the aqueous medium, in the last column of Table 6, S

co-sol (w)/S

co-sol (b) ratios are

given. It is seen that the Sco-sol (b)

/Sb and S

co-sol (b)/S

w ratios

are much smaller in phosphate buffer medium. Also the S

co-sol (w)/S

co-sol (b) ratios, in the presence of co-solvent

are again much higher than the corresponding Sw

/Sb

ratios in the absence of co-solvent in most cases. This again indicates that the effect of co-solvent is highly dependent on the medium used. The behavior of ros-iglitazone in the presence of 20% PEG, PG and glycerol was exceptional.

Significance of solubility data

The commonly used doses of the drugs used in the present work and the minimum solubility of the drug required for 5 mL dose are provided in Table 7. For each drug, solvents with drug solubility greater than that required for 5 mL dose are also given in Table 7. The data can be useful for the development of various drug formulations.

Conclusions

Significant enhancement in the solubility of the studied antidiabetic drugs can be achieved by the use of co-solvents. The synergistic effect of buffer and co-solvents in the case of sulfonylureas and repaglinide resulted in enormous increase in solubility. Solubility greater than 10 mg/mL in the case of gliclazide, repaglinide and gli-tazones and about 1–5 mg/mL in the case of glipizide, glimepiride and glyburide could be attained. In the case of glitazones, presence of co-solvent alone caused signifi-cant enhancement of aqueous solubility; the presence of

buffer had negative effect on the solubilization potential of the co-solvents.

Acknowledgment

Declaration of interest: The authors report no conflicts of interest.

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