Solubility of pioglitazone hydrochloride in ethanol, N-methyl pyrrolidone, polyethylene glycols and water mixtures at 298.20 °K.

BACKGROUND AND THE PURPOSE OF THE STUDY: Solubility of pharmaceuticals is still a challenging subject and solubilization using cosolvents is the most common technique used in the pharmaceutical industry. The purpose of this study was reporting and modeling the experimental molar solubility of pioglitazone hydrochloride (PGZ-HCl) in binary and ternary mixtures of ethanol (EtOH), N-methyl pyrrolidone (NMP), polyethylene glycols (PEGs) 200, 400, 600 and water along with the density of saturated solutions at 298.2 °K.
METHODS: To provide a computational method, the Jouyban-Acree model was fitted to the solubilities of the binary solvents, and solubilities of the ternary solvents were back-calculated by employing the solubility data in mono-solvents. In the next step, the ternary interaction terms were added to the model and the prediction overall mean percentage deviation (MPD) of the ternary data was reduced. Also a previously proposed version of the model was used to predict the solubility of PGZ-HCl in binary and ternary mixtures employing the experimental solubility data in mono-solvents.
RESULTS: The overall MPD of the model for fitting the binary data and predicted data of ternary solvents were 2.0 % and 50.5 %, respectively. The overall MPD of the predicted solubilities in ternary solvents using the ternary interaction terms in the model was 34.2 %, and by using the proposed version of the Jouyban-Acree model for binary and ternary data the overall correlation and prediction errors were 18.0 and 15.0 %, respectively.
CONCLUSION: The solubility of PGZ-HCl was increased by addition of EtOH, NMP, PEGs 200, 400 and 600 to aqueous solutions. The reported data extended the available solubility data of pharmaceuticals which are crucial in formulation of liquid dosage forms. The constants of the Jouyban-Acree model using the generated data are also reported which provides the possibility of solubility prediction in other solvent mixtures and temperatures.

INTRODUCTION

Pioglitazone (PGZ) is a non-polar drug and cannot effectively break down the lattice structure of water and hence its aqueous solubility is low. Different techniques are used to enhance the aqueous solubility of drugs including salt formation (1), cocrystal formation (2), addition of cosolvents (3), hydrotropes (4), surface active agents (5) and ionic liquids (6). PGZ hydrochloride (PGZ-HCl) is used in pharmaceutical formulations, however the aqueous solubility of PGZ-HCl is still low and reports of a number of investigations deal with solubilization of PGZ or PGZ-HCl (7, 8). In continuation of our systematic studies on the solubility of drugs, in this study the solubility of PGZ-HCl in non-aqueous binary mixtures of ethanol (EtOH), N-methyl pyrrolidone (NMP) and polyethylene glycols (PEGs) 200, 400 and 600 and their aqueous ternary mixtures at 298.2°K were investigated. The generated data could be used to develop more accurate cosolvency models. The solubility of PGZ-HCl in the mixed solvents was calculated using numerical methods and the accuracy of different methods are discussed by comparing the percentage deviations between calculated and experimental solubilities.

MATERIAL AND METHODS

PGZ-HCl (99.8 w/w %) was purchased from Osveh Pharmaceutical Company (Tehran, Iran). PEG 400 and PEG 600 were kindly gifted by Dana Pharmaceutical Co. (Tabriz, Iran), EtOH (99.9 w/w %) and PEG 200 (99.5 w/w %) were purchased from Merck (Germany), methanol (99.8 w/w %) was purchased from Caledon (Canada) and double distilled water was used for preparation of the solutions. Solubility of PGZ-HCl in the solvent mixtures was determined using Shake-flask method of Higuchi and Connors (9). The generated solubility data was modeled using the Jouyban-Acree model. The model for calculation of the solubilities of drugs in binary solvent mixtures at different temperatures is (10):where is the molar solute solubility in the solvent mixtures at temperature T, w1 , and w2 are the mass fractions of the solvents 1 and 2 in the absence of the solute, and denote the molar solubility of the solute in the solvents 1 and 2, respectively. The Jouyban-Acree model provides accurate descriptions for other properties of the solvent mixtures including the solvatochromic parameters (11). The model for representing the solubility of drugs in ternary solvent mixtures based on sub-binary interaction terms is:where is the solute (mol·l-1) solubility in the solvent 3 (water) at temperature T, and w is the mass fraction of the solvent 3 in the absence of the solute. To provide more accurate data, it is possible to include ternary interaction terms as:

The mean percentage deviation (MPD) was used to check the accuracy of the fitted and predicted values and was calculated using:where N is the number of data points in each set.

RESULTS AND DISCUSSION

Table 1 lists the experimental solubilities of PGZ-HCl in the investigated non-aqueous binary mixtures along with the density of saturated solutions at 298.20 °K. When these binary data sets were fitted to equation I, the model constants (i.e. J , J , and J )could be computed along with the MPD of the back-calculated solubilities. These findings for three investigated data sets in this work and the similar results collected from previous works are reported in table 2. The model provides a very good mathematical description of the experimental solubility data and the overall MPD for all reported data in the present and previous studies is 5.1 %. The corresponding value for three binary sets of this work is 2.0 %.

Table 1

Mole per liter solubility of pioglitazone hydrochloride in various binary mixtures and density of saturated solutions at 298.20 °K.

W 1	Cm,TSat(Molar)	Density (g·cm-3)
		EtOH + PEG 200
0.000	0.0191	1.1454
0.200	0.0271	1.0547
0.400	0.0426	0.9764
0.600	0.0337	0.8879
0.800	0.0231	0.8158
1.000	0.0227	0.8340
		NMP + PEG 200
0.000	0.0191	1.1454
0.200	0.0231	1.1371
0.400	0.0511	1.1186
0.600	0.1206	1.1062
0.800	0.2377	1.0877
1.000	0.5082	1.1530
		NMP + PEG 600
0.000	0.0242	1.1599
0.100	0.0264	1.1590
0.200	0.0369	1.1585
0.300	0.0520	1.1580
0.400	0.0649	1.1575
0.500	0.1087	1.1570
0.600	0.1543	1.1565
0.700	0.2111	1.1560
0.800	0.2803	1.1550
0.900	0.3814	1.1540
1.000	0.5082	1.1530

Table 2

The numerical values of the constants of the Jouyban-Acree model, the mean percentage deviations (MPDs) for the fitted model of binary solvents at 298.2 K, and the number of data points (N).

Solvent system	J0	J1	J2	MPD (%)	N
EtOH + PEG 200	344.778	-214.596	-544.856	2.8	6
EtOH + PEG 400	396.833	-214.247	-272.687	2.6	8
EtOH + water	1068.183	371.904	2680.788	13.8	10
NMP + PEG 200	-108.357	251.214	-336.276	0.4	6
NMP + PEG 400	-31.885	254.652	-347.558	1.5	7
NMP + PEG 600	-27.607	175.414	-137.760	2.9	11
NMP + water	284.802	-118.977	1592.235	13.6	14
PEG 200 + water	355.814	-146.604	1804.685	1.6	6
PEG 400 + water	688.422	-331.664	1253.150	6.5	8
PEG 600 + EtOH	366.947	-103.801	-391.432	3.2	11
PEG 600 + water	802.666	-334.631	1374.847	5.8	11
PEG 600 + water	820.312	-367.334	1418.858	6.2	11
PG* + PEG 200	288.959	NS**	NS	2.7	6
PG + PEG 400	461.517	NS	NS	5.8	8
PG + PEG 600	425.700	NS	NS	4.9	11
PG + water	949.811	-728.097	686.448	7.5	9
			Overall MPD (%)	5.1

PG: Propylene glycol.

NS: Not significant.

Table 3 lists the experimental solubility of PGZ-HCl in a number of ternary aqueous mixtures and the density of saturated solutions at 298.20 °K. This data could be predicted by the model constant of sub-binary solvents using equation II through incorporation of the J terms from table 2. The obtained MPD values for the predicted solubility data of PGZ-HCl in ternary solvents are listed in table 4. To provide more accurate predictions, it is possible to include ternary solvent interaction terms to the model, but it requires more experimental efforts, i.e. measurement of a number of solubility data in ternary solvent mixtures. The obtained ternary solvent model constants and the resulting MPD values are listed in table 4, in which the overall MPD of 34.2 % was obtained. As a general conclusion, the solubility of PGZ-HCl in a number of binary and ternary solvents has been reported which could be used in the pharmaceutical industry.

Table 3

Solubility of pioglitazone hydrochloride mole per litre in various ternary mixtures and density of saturated solutions at 298.20 °K.

w1	w2	Cm,TSat (Molar)	Density (g·cm-3)
EtOH + PEG 200 + Water
0.100	0.100	0.0115	1.0037
0.200	0.100	0.0208	0.9801
0.200	0.200	0.0692	1.0101
0.100	0.400	0.0390	1.0593
0.300	0.200	0.0550	0.9865
0.100	0.500	0.0226	1.0529
0.300	0.300	0.0355	0.9951
0.500	0.100	0.0550	0.9381
0.200	0.500	0.0568	1.0272
0.400	0.300	0.0931	0.9587
0.600	0.100	0.1064	0.9164
0.200	0.600	0.0745	1.0527
0.400	0.400	0.0798	0.9772
0.600	0.200	0.1490	0.9318
0.100	0.800	0.0603	1.0873
0.300	0.600	0.0514	1.0418
0.500	0.400	0.0399	0.9700
0.700	0.200	0.0355	0.9382
* NMP + PEG 200 + Water
0.100	0.100	0.0145	1.0712
0.200	0.100	0.0174	1.0650
0.200	0.200	0.0295	1.0877
0.100	0.400	0.0421	1.1145
0.300	0.200	0.0727	1.0712
0.100	0.500	0.0279	1.1227
0.300	0.300	0.0860	1.0897
0.500	0.100	0.1259	1.0710
0.200	0.500	0.1251	1.1330
0.400	0.300	0.2590	1.1165
0.600	0.100	0.4080	1.0980
0.200	0.600	0.1082	1.1557
0.400	0.400	0.2164	1.1351
0.600	0.200	0.3228	1.1145
0.100	0.800	0.0851	1.1824
0.300	0.600	0.1224	1.1680
0.500	0.400	0.1082	1.1495
0.700	0.200	0.2164	1.1309
NMP + PEG 400 + Water
0.100	0.100	0.0169	1.0733
0.200	0.100	0.0204	1.0671
0.200	0.200	0.0359	1.0877
0.100	0.400	0.0474	1.1145
0.300	0.200	0.0780	1.0733
0.100	0.500	0.0301	1.1227
0.300	0.300	0.0896	1.0939
0.500	0.100	0.1384	1.0721
0.200	0.500	0.1392	1.1351
0.400	0.300	0.2838	1.1206
0.600	0.100	0.4648	1.0980
0.200	0.600	0.1135	1.1598
0.400	0.400	0.2217	1.1371
0.600	0.200	0.3335	1.1145
0.100	0.800	0.0904	1.1866
0.300	0.600	0.1312	1.1680
0.500	0.400	0.1153	1.1515
0.700	0.200	0.2359	1.1351
NMP + PEG 600 + Water
0.100	0.100	0.0375	1.0774
0.100	0.200	0.0703	1.0856
0.200	0.100	0.0520	1.0712
0.300	0.100	0.0805	1.0630
0.200	0.200	0.0865	1.0877
0.100	0.300	0.0732	1.1062
0.100	0.400	0.0687	1.1186
0.200	0.300	0.0953	1.0897
0.300	0.200	0.1029	1.0774
0.400	0.100	0.1104	1.0609
0.100	0.500	0.0421	1.1227
0.200	0.400	0.0816	1.1124
0.300	0.300	0.1304	1.0980
0.400	0.200	0.1215	1.0815
0.500	0.100	0.1641	1.0733
0.100	0.600	0.0550	1.1474
0.200	0.500	0.2412	1.1392
0.300	0.400	0.2696	1.1289
0.400	0.300	0.3459	1.1206
0.500	0.200	0.7788	1.1103
0.600	0.100	0.5694	1.1021
0.100	0.700	0.1472	1.1742
0.200	0.600	0.1477	1.1618
0.300	0.500	0.2536	1.1536
0.400	0.400	0.2648	1.1412
0.500	0.300	0.3374	1.1248
0.600	0.200	0.3920	1.1186
0.700	0.100	0.5783	1.1103
0.100	0.800	0.1014	1.1866
0.200	0.700	0.2003	1.1783
0.300	0.600	0.1997	1.1721
0.400	0.500	0.2496	1.1618
0.500	0.400	0.3271	1.1557
0.600	0.300	0.3904	1.1454
0.700	0.200	0.4962	1.1392
0.800	0.100	0.6617	1.1309

N-methylpyrrolidone

Table 4

The numerical values of the ternary constants (J"' ) of the Jouyban-Acree model, the mean percentage deviations (MPDs) for the fitted model of binary solvents at 298.2 K and number of data points (N).

Solvent system	J'''0	J'''1	J'''2	MPD (%)*	MPD (%)**	N
EtOH + PEG 200 + Water	1751.699	-3297.830	NS	33.3	42.3	18
NMP + PEG 200 + Water	5840.418	NS***	NS	35.3	58.3	18
NMP + PEG 400 + Water	4769.598	NS	NS	36.0	51.5	18
NMP + PEG 600 + Water	6048.601	NS	NS	31.5	64.9	36
EtOH + PEG 400 + Water	1642.704	NS	NS	34.9	35.3	18
		Overall MPD (%)		34.2	50.5

MPD for equation III.

MPD for equation II.

NS: Not significant.