Ind. Eng. Chem. Res. 2003, 42, 1821-1823
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RESEARCH NOTES Solubilities of Imipramine HCl in Supercritical Carbon Dioxide Eliana Jara-Morante, David Suleiman, and L. Antonio Este´ vez* Department of Chemical Engineering, University of Puerto Rico, Mayagu¨ ez, Puerto Rico 00681-9046
The solubility of imipramine HCl in supercritical carbon dioxide has been measured experimentally by a gravimetric technique. An ISCO extraction apparatus was modified to carry out the measurements. It consists of a syringe pump, a thermostatic chamber, an equilibrium cell, a variable-flow-rate restrictor, and an ice trap. Experiments were conducted by allowing the supercritical carbon dioxide to slowly flow through the cell, where the imipramine HCl had been previously loaded. The pressure was kept constant, controlled by the pump, and so was the flow rate, controlled by the restrictor. The amount of solute collected in the trap was measured in two different ways for consistency: gravimetrically and by dissolving the solute collected in methanol and measuring the concentration spectrophotometrically. The amount of solvent was measured by the difference in volume readings in the syringe pump (calculating the density of carbon dioxide at the pump conditions); this value was also determined by measuring an average flow rate of the expanded solvent and the time of the run. A total of 52 measurements were done. Two five-point isotherms, at 40 and 50 °C, were obtained for pressures ranging from 30 to 50 MPa. Measured solubilities were within the range (5-10) × 10-6 mole fraction. These are the only published data for this system. Introduction This work is part of a long-range effort to determine whether current isolation steps in chemical plants producing drugs can be replaced by processes involving supercritical fluids (SCFs), e.g., supercritical-fluid extraction. A crucial element in this endeavor is a broad solubility database including various families of drugs in conventional and less conventional SCFs. This paper deals with a member of the antidepressant family, imipramine HCl. To the authors’ knowledge, these are the only solubility data reported for this system. Imipramine HCl (CAS 113-52-0) is one of the main tricyclic drugs used in the treatment of depression. Many of its properties are closely related to its structure, shown in Figure 1. Its chemical groups (aromatic, amine, and aliphatic) provide this molecule with structural diversity and unique physical and chemical properties. The free-base form, C19H24N2, is a lipid insoluble in water and soluble in ether, while the salt form, C19H24N2‚HCl, is soluble in water and insoluble in ether.
Figure 1. Structure of imipramine HCl.
Experimental Section The experimental apparatus (a commercial extraction equipment, ISCO SFX 2-10, modified for this application) is shown in Figure 2. A typical experimental run was carried out by placing a measured amount of solids (solute) in the equilibrium cell and allowing the supercritical solvent to circulate through the cell slowly enough to ensure equilibrium. The pressure was controlled by the syringe pump (ISCO 260D) and the
Figure 2. Experimental apparatus.
* To whom correspondence should be addressed. Tel.: 787265-3809. Fax: 787-265-3818. E-mail:
[email protected].
temperature of the solvent leaving the pump was measured by a thermocouple (Omega DP24-T). The flow
10.1021/ie0109105 CCC: $25.00 © 2003 American Chemical Society Published on Web 03/22/2003
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Ind. Eng. Chem. Res., Vol. 42, No. 8, 2003
Table 1. Characteristics of the Materials Used in the Present Work material
formula
M [g/mol]
Tm [K]
purity [%]
supplier
imipramine HCl methanol, HPLC grade CO2, SFC grade
C19H24N2‚HCl CH3OH CO2
316.87 32.04 44.01
447
99.99 99.8 99+
Sigma Chemical Co. EM Science Scott Specialty Gases
Table 3. Solubility of Imipramine HCl y × 106
y × 106
P [MPa]
40 °C
50 °C
P [MPa]
40 °C
50 °C
30 35 40
6.4 7.6 9.0
6.1 8.8 8.2
45 50
9.9 5.1
8.0 6.4
Figure 3. Solubility of naproxen in CO2 at 50 °C. Table 2. Operating Conditions condition
value
solute loaded [mg] average solvent flow rate [mL/min] pressure [MPa] temperature [°C] run time [h]
40 0.09-0.18 30-50 40 and 50 6-7
rate through the cell, maintained constant during the experiment, was controlled by a variable restrictor at the end of the extractor. The expanded solvent flow rate was measured by a bubble flowmeter (Hewlett-Packard 0101-0113) at regular intervals. The amount of solute collected in the trap or reception tube was measured in two ways: gravimetrically and by dissolving the solute in methanol and measuring the concentration spectrophotometrically. The amount of solvent was measured by the difference in volume readings in the syringe pump (calculating the density of carbon dioxide at the pump conditions). In earlier runs, this was compared to the amount of solvent calculated from the average expanded flow rate and run time. The solvent flow rate was low enough to ensure phase equilibrium in the cell, and thus extraction runs were rather long. The imipramine was recovered in a known amount of methanol, and the mass collected was quantified with a spectrophotometer (Spectronic Genesys 5). The mass of imipramine collected was also measured gravimetrically (Sartorious balance model Research R200D, with a (10-µg accuracy). Before the imipramine measurements were conducted, the apparatus was validated by measuring the solubility of naproxen in carbon dioxide at 50 °C and two pressures, 16.0 and 19.3 MPa. These results were compared to literature measurements.1 Figure 3 shows such a comparison, where good agreement is observed. The materials used in this work, along with their properties and sources, are listed in Table 1, while typical operating conditions are shown in Table 2. Results Two solubility isotherms for imipramine HCl in supercritical carbon dioxide were obtained at 40 and 50
Figure 4. Solubilities of imipramine HCl in CO2.
°C and for pressures ranging from 30 to 50 MPa. The solubilities obtained, expressed as mole fraction, are presented in Table 3 and Figure 4. A total of 52 measurements (runs) were carried out, and thus each data point reported is the average of several replicates (about five). As explained in the Discussion section, the error associated to each data point was estimated to be about 30%, and the error bars in Figure 4 have been drawn accordingly. Discussion The solubility of imipramine HCl was lower than expected, based on the results for drugs with similar molar masses and melting points, as seen in Table 4. A possible explanation for this might be related to the effect of HCl. This effect, primarily over the two tertiary amines of the imipramine molecule, might be inhibiting the solubility in CO2. Also, the polarity induced by the HCl group on the imipramine molecule may hinder the dissolution in the nonpolar CO2, which would not be the case with the lipophilic imipramine free base. Another interesting feature of these results is the decreasing solubility beyond a given pressure. This might be attributed to a limitation of the technique, although it agrees with the observations of Vandana and Teja,2 for paclitaxel in CO2. This investigation’s results can be contrasted or compared to solubility data in carbon dioxide for pharmacological drugs previously measured. (The scarcity of these data is noteworthy.) Table 4 lists such data arranged by decreasing solubility. As can be seen, the solubilities span several orders of magnitude (10-7-10-2 mole fraction) with no apparent relation to the solute molar mass or volatility (as indicated by the melting point).
Ind. Eng. Chem. Res., Vol. 42, No. 8, 2003 1823 Table 4. Solubility of Drugs in Supercritical CO2 substance lovastatin3 cholesterol4 ketoprofen5 nimesulide5 monocrotaline6 piroxicam5 naproxen1 imipramine HCla paclitaxel2 monensin7 a
formula C24H36O5 C27H46O C16H14O3 C13H12N2O5S C16H23NO6 C15H13N3O4S C14H14O3 C19H24N2‚HCl C47H51O14 C36H61O11Na
M [g/mol] 404.5 386.7 254.3 308.3 325.4 331.3 230.3 316.9 853.9 693.0
Tm [K] 421.65 367.65 421.65 469.15 447.15 489.15
P [MPa] 12.4-40.9 10-25 10-22 10-22 8.9-27.4 10-22 8.9-19.3 30-50 14-35 14-40
y 10-4-6.0
9.0 × × 10-2 1.0 × 10-5-1.4 × 10-4 7.8 × 10-6-1.5 × 10-4 8.5 × 10-6-9.8 × 10-5 6.0 × 10-6-4.4 × 10-5 3.7 × 10-6-4.3 × 10-5 2.0 × 10-6-3.2 × 10-5 5.0 × 10-6-9.9 × 10-6 1.1 × 10-6-5.7 × 10-6 5.8 × 10-7-3.0 × 10-6
This work.
The measurement of rather low solubilities, such as those observed in this work, is extremely difficult. Undoubtedly, the main source of error is the quantification of the collected mass of solute. Two factors are involved here: first, the intrinsic error associated with gravimetric measurement of low masses and, second, precipitation of solids in the lines, which even in the order of microgramssnormally considered negligibles may greatly affect the results. These factors provide an explanation of the errors observed experimentally and are indirectly quantified through the variance of the replicates. Other sources of error (e.g., pressure and temperature) were similar to those seen in conventional solubility methods.1 On the basis of this analysis, the experimental error associated with the measurements in this work has been estimated to be 30%. A detailed error analysis is presented elsewhere.8 The results presented here lend themselves to speculation on crossover points. Again, the unusually high pressures in these measurements, combined with rather large error bars, preclude further discussion and prompt further experimental evidence. Conclusions The solubility of imipramine HCl in supercritical carbon dioxide has been measured experimentally by a gravimetric technique. Although the solubility data measured were low (10-6 mole fraction), they could suggest possible reverse extraction applications (i.e., solubilizing everything else but the drug of interest). Also, the chemical functionalities studied increase the database and the knowledge of phase equilibria in supercritical carbon dioxide. This is especially important as new pharmacological drugs emerge with increasing purity requirements. Further investigations could be aimed at the effect of crystal structure, especially with polymorphic drugs.
Acknowledgment The National Science Foundation is gratefully acknowledged for the financial support of this investigation (NSF Grant CTS-9634117). Literature Cited (1) Ting, S. S.; Macnaughton, S. J.; Tomasko, D. L.; Foster, N. R. Solubility of Naproxen in Supercritical Carbon Dioxide with and without Cosolvents. Ind. Eng. Chem. Res. 1993, 32, 14711481. (2) Vandana, V.; Teja, A. S. The Solubility of Paclitaxel in Supercritical CO2 and N2O. Fluid Phase Equilib. 1997, 135, 8387. (3) Larson, K. A.; King, M. L. Evaluation od Supercritical Fluid Extraction in the Pharmaceutical Industry. Biotechnol. Prog. 1986, 2 (2), 73-82. (4) Yun, S. L. J.; Liong, K. K.; Gurdial, G.; Foster, N. R. The Solubility of Cholesterol in Supercritical Carbon Dioxide. Ind. Eng. Chem. Res. 1991, 30 (11), 2476-2482. (5) Macnaughton, S. T.; Kikic, I.; Foster, N.; Alessi, P.; Cortesi, A.; Colombo, I. Solubility of Anti-Inflammatory Drugs in Supercritical Carbon Dioxide. J. Chem. Eng. Data 1996, 41, 1083-1086. (6) Schaeffer, S. T.; Zalkow, L.; Teja, A. S. Extraction and Isolation of Chemo-therapeutic Pyrrolizidine Alkaloids from Plant Substrates. A Novel Process Using Supercritical Fluids. In Supercritical Fluid Science and Technology; Johnston, K. P., Penninger, J. M. L., Eds.; ACS Symposium Series 406; American Chemical Society: Washington, DC, 1989; pp 416-433. (7) Maxwell, R. J.; Hampson, J. W.; Cygnarowicz, M. L. Solubility Measurements of Certain Antibiotic Drug Classes in Supercritical Fluids. Proc. 2nd Int. Symp. Supercrit. Fluids 1991, 143-145. (8) Jara-Morante, E. The solubility of Imipramine HCl in Supercritical Carbon Dioxide. M.S. Thesis, University of Puerto Rico, Mayagu¨ez, Puerto Rico, 1999.
Received for review November 8, 2001 Revised manuscript received March 15, 2002 Accepted March 26, 2002 IE0109105
