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Solubility of Paracetamol in Pure Solvents
Roger A. Granberg, and ke C. Rasmuson
J. Chem. Eng. Data, 1999, 44 (6), 1391-1395• DOI: 10.1021/je990124v • Publication Date (Web): 11 November 1999 Downloaded from http://pubs.acs.org on April 20, 2009

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The reproducibility/repeatability was determined in three different solvents (water. water bath stability. excess PA was allowed to settle for at * To whom correspondence should be addressed. Solubility studies on paracetamol in organic solvents have been carried out by. was calculated by eq 1. 10. and weighing is estimated to be 0. Germany) having an uncertainty of (0. equilibrium was reached by cooling (supersaturated case) or heating (undersaturated case) the solution to the desired temperature in the presence of excess solid phase. 1990). was determined.2 µm). The temperature was kept within (0. showing that that there were no particles remaining in the clear solution. and three new samples were withdrawn.. Paracetamol is soluble in alcohols. (1984) determined the solubility of PA in water in the range from 5 to 70 °C. The vials had Teflon septums to prevent solvent evaporation during the weighing procedure. Royal Institute of Technology.00 © 1999 American Chemical Society Published on Web 11/11/1999 . Chem. With only the solid residue remaining in the sample vials. Paracetamol has a very low solubility in nonpolar and chlorinated hydrocarbons such as toluene and carbon tetrachloride whereas the solubility is very high in solvents of medium polarity such as N. and diethylamine. and near the top of the flask. Data 1999.2 µm) samples were also taken. and ethyl acetate) and Subramanyam et al. In the present work. deionized.. Wertheim. including water. The water used was distilled. and butanol) at 25 °C. 2-propanol.02 °C of the desired temperature and was checked with a Pt-100 resistance thermometer. expressed in g of solute/ kg of solvent. Romero et al. respectively) by cooling a solution to 30 °C in the presence of excess solid phase and taking three solubility samples. The Pt-100 thermometer used was calibrated against a calibrated mercury precision thermometer (Thermo-Schneider. The solubility.1021/je990124v CCC: $18. CS ) 103(mvdr . (1996) (in water. spanning a wide range of polarity.J. Introduction Solubility data of bioactive compounds have a broad application and importance in the pharmaceutical industry. and solvent mixtures (e. in the middle.. A sample of the clear saturated solution (approximately 10 cm3) was transferred with a preheated syringe into a previously weighed sample vial with mass mv. ethanol.mv)/(mvs . mvs. i.g. Grant et al. solubility data for paracetamol in 26 different pure solvents. The uncertainty due to temperature measurements. and filtered (0. are reported in the temperature range -5 to +30 °C. Then the constant “dry residue” mass.01 °C. fine powder of pharmaceutical grade. and the activity coefficient in the saturated solutions is estimated. 44. ethanol. No differences were found.g. Erlenmeyer flasks (250 cm3) with a Teflon-coated magnetic stirrer were filled with an excess of PA in a solvent (Table 1). Rasmuson* ° Department of Chemical Engineering and Technology. Samples from the clear solution were taken at the bottom. and 1133 g of PA/kg of solvent. 135. 1391-1395 1391 Solubility of Paracetamol in Pure Solvents Roger A. Granberg and Ake C. was measured. propanol. the temperature is raised to 105 °C. and after 3 days the vials were placed in a desiccator to attain room temperature. the solubility was not affected by whether equilibrium was approached from an undersaturated or from a supersaturated solution. but the solubility decreases with an increase in the length of the carbon chain in the n-alcohol homologous series (methanol to 1-octanol).15%. mvdr. e. The ideal solubility of paracetamol is calculated.3% on dry basis determined as specified by the European Pharmacope) were used without further purifi´ cation.se. SE-10044 Stockholm. (mv and mvs both denote masses without the Teflon septum. The drying of solvents having a boiling point >120 °C was performed at 40 °C in a vacuum oven. The solubility of paracetamol in water is much lower than in other polar solvents such as the alcohols. Eng. The flasks were placed in the thermostat bath and agitated for at least 72 h at each temperature. Filtered (0. (1992) (in methanol.kth. and dimethyl sulfoxide with solubilites of 17. The experimental setup consists of a thermostatic water bath standing on a serial magnetic stirrer. the septums are removed and the solvent was allowed to evaporate in an air oven at 40 °C for approximately 1 week for solvents where the boiling point is below 120 °C. Experimental Section The 25 solvents listed in Table 1 and paracetamol (Astra Production Chemicals AB.) Then. binary and ternary mixtures) can usually be employed in a particular crystallization process during the manufacturing of pharmaceuticals (Grant and Higuchi.e. After the equilibration. It is also used as an intermediate in the manufacture of azodyes and photographic chemicals.mvdr) (1) The state of saturation was approached from both supersaturation and undersaturation. The mass of the sample vial with the saturated solution. 100. As can be seen in Table 3.N-dimethylformamide. E-mail: rasmuson@ ket. dimethyl sulfoxide. showing that that the solutions were homogeneous. least 4 h with no agitation. Sweden The solubility of paracetamol (4-hydroxyacetanilide) in 26 solvents in the temperature range from -5 to +30 °C is reported. The solution was then cooled to 20 °C before it was heated to 30 °C. A variety of pure solvents. Paracetamol (PA) is an important analgesic and antipyretic agent.

This value is in agreement with sample no. p.30 0.02 1132. CS. 98%) N.35 1.61 0. p. 0.a.30 9.18 3.08 0.41 1070 135.78 1.30 17.83 1316.22 0. p. p. Table 2.27 0.05 1.00 2 water 7.45 1 27.09 1 239.32 1 121.d.39 1145 134.56 82.92 2 265.34 1 toluene 0.d.98 0. 44.75 2 55.73 0.a.37 0. purum) dimethyl sulfoxide (Riedel-De Haen.a.38 1165 135.27 1 99.46 1 5.03 4 332.14 0.5309 loss/residue* [%] 0.4-dioxane (Merck.4149 2.a.35 2.5329 0 0 m1-octanol 0 0 0 5.96 0.48 4.81 190.31 0.54 3.66 1. p. at 30 °C are calculated from eq 3.a.21 0.05 0.37 17. Reproducibility/Repeatability Experiments of the Solubility Determinations solvent 2-propanol water dimethyl sulfoxide samples taken when cooled to 30 °C 135.41 0.77 135.a.d.38 1157 samples taken when heated to 30 °C 135.60 0.83 17.) ethyl acetate (Merck.27 1 0.27 0.71 37.) 1-butanol (Merck.43 38.09 8.d. .28 0.02 38 n 6 6 5 Table 4.40 5 141.23 1.16 4 79.23 0.d.a. No.39 0.78 297.43 27.90 0. n CS 0 °C s.82 49. p. p.61 232.96 0.44 1 11.63 0.06 6 8.a.08% in sample nos.31 0.03 2 71. Five samples were prepared where known amounts of PA and/ or some selected solvents with high boiling points (1-octanol and dimethyl sulfoxide) were added (Table 4).91 1 119.) dichloromethane (Merck.22 2 69.01 17.9635 3. 4 and 5).38 1 1-butanol 47.57 17.d.69 2 96.12 3 57.64 67. [g/kg] 0.08 0. and slow cooling in a desiccator.a.37 0.61 108.5066 2.) acetonitrile (Merck. of Paracetamol in Different Solvents at Temperatures between -5 and +25 °C (Solubilities at 30 °C Are Given in Table 1) with the Corresponding Standard Deviation (s.N-dimethylformamide (Merck.51 2 ethylacetate 4.05 0.18 0.44 0.58 73.4161 2. CS. with an excess of paracetamol.) ¨ carbon tetrachloride (Merck.20 3.d.73 32.a.63 3 215.6749 weight [g] after the drying procedure mparacetamol 0.12 2 9.06 0.07 3 10. Vol.5063 2.75 2.2-ethanediol (Merck.42 0.11 1 209.05 2 97. and 72 h.) 2-butanone (Merck.81 503.75 144. No detectable residue was found on evaporation of these pure solvents (sample nos.87 2.39 371.62 0.75 3. Given in g of Paracetamol/kg of Solvent.31 1 69.10 0.35 134. The water content of the paracetamol used in this work. of Paracetamol in Different Solvents at 30 °C with the Corresponding Standard Deviation (s. p. the loss of paracetamol during the drying procedure is <0.) 1-pentanol (Merck.a. As can be seen in Table 4. n CS 10 °C s.20 4 5.03 2 0.30 0.65 69.11 2 19.5%) 1.a.a.26 431.95 0.02 0. On the basis of this error analysis. p. p. Error Analysis of the Drying Procedure (Loss on Drying/Residue after Evaporation) added amounts [g] before the drying procedure no.48 2. Given in g of Paracetamol/kg of Solvent.71 99. p. Solubility.10 0.a. according to specifications (Astra Production Chemicals AB).72 0. n CS 15 °C s. These samples went through the same drying procedure as the solubility samples with 1 week at 40 °C. n CS 12.81 155.26 17. p.39 10.d.09 2 methanol 174.) 1. p. >99.30 0.) 1-octanol (Merck. 48. p.) ¨ acetic acid (Merck.13 5.a.78 1 6.65 1.23 1.42 0.36 1 Table 3. n CS 5 °C s. 0.39 0.02 1 87. 3 days at 105 °C.32 0.56 1 129.10 0. 1-3.54 0.24 4 79.32 1.a.1392 Journal of Chemical and Engineering Data.01 n 5 4 3 3 3 2 7 3 3 2 CS 25 °C s.37 20 °C s.99 17.21 0.) acetone (Merck. p.) ethanol (Kemetyl AB.90 1012. p. 24.a.00 Activity coefficients.47 111.34 s.19 0.d.40 1 1-propanol 65.22 0.13 0.) chloroform (Riedel-De Haen.44 0.01 93. n 14.a.09 108.) and the Number of Samples (n) -5 °C solvent CS s.52 23.00* A saturated solution of paracetamol in acetone was cooled from 30 to 20 °C.88 1 72. is <0.4893 0 6.31 0.06 2 7.) toluene (Merck.21 0. 6.04 2.07 88.97 0.) 2-propanol (Merck.34 0.a.41 0.) tetrahydrofuran (JT Baker. 1 in Table 4. Solubility. p.11 17.41 1126 CS [g/kg] 135. purum) 1-propanol (Merck.44 1 15.77 1 2-propanol 64. The results show that the solutions had reached equilibrium after about 5 h.77 7.) 1-hexanol (Merck.34 6 62.60 1. 1999 Table 1.67 0.24 2.) 1-heptanol (Sigma.a.55 1 51.34 n 7 5 4 2 4 5 2 2 4 4 3 7 4 3 4 3 5 5 2 3 5 3 1 1 1 2 γS 43. The supplier and the grade (purity) of the solvent are also given.29 1 acetone 50.45 0.a. the overall uncertainty of the solubility measurements is estimated to be less than 1%.d. p.32 1 0.37 1 acetonitrile 9.39 1133 s.43 1 ethanol 118.21 1 63.00 17.54 1 0.35 2 191.08 10.1% (loss on drying at 105 °C). p. 1 2 3 4 5 mparacetamol 0.30 132. γS.24 0.71 3 9.89 0.17 2.15 1 83.31 4.00* 0.62 1 88.83 0.60 2 171.d. and the approach to equilibrium at 20 °C was evaluated by taking samples after 2. p. p.06 14. 5.4613 0 mdimethyl sulfoxide 0 6.82 1 156.10 4 13.41 3 78.) a CS 17.78 77.) 4-methyl-2-pentanone (Merck.48 0.) diethylamine (Sigma.22 0.) and the Number of Samples (n)a solvent water methanol (Merck.05 10.

ethyl acetate. A suitable standard state for our purposes is the solute as a pure supercooled liquid at the same temperature (T) as the solution in question.. The results in the present work on the solubility in alcohols. 2-propanol. Figure 3 shows how the solubility increases with increasing temperature.e. the activity of the pure solute in the solid state (asolid) can be S expressed as (Walas. EN-values (Reichardt.. a Raoult’s law type of standard state. The difference (Cp. implying that it is unlikely that paracetamol is undergoing any polymorphic transitions during the solubility determinations. 1985. the chemical potential of the solute in the solution is equal to that of the solute in the pure solid state. acetonitrile. 6. if the vertical axis in Figure 1 is made linear instead of logarithmic..9) or Subramanyam et al. 1990). CS. between the heat capacity of the hypothetical supercooled liquid form Cp. s. Results and Discussion Tables 1 and 2 list experimental results over the solubility of paracetamol in the 26 pure solvents studied. The solubility of PA in water is much lower than that in other polar solvents such as the alcohols. O. (1996). Based on rigorous thermodynamics. Figure 2. methanol. in which P is pressure .l .9).l . small amounts of water in ethanol significantly increase the solubility (Prakongpan and Nagai.d.Vs dP RT (2) where ∆H f is the enthalpy of fusion at the triple point Ttp tp and R is the gas constant.e. 2-butanone. i.. 1990). where. which is the usual pharmaceutical material (with melting points about 170 °C). as shown in Figure 2. 1-butanol.e. e. Furthermore. of paracetamol at 30 °C versus solvent polarity (E N-values. CS. T The EN-value is derived from the transition energy for the T longest wavelength in UV/vis spectra solvatochromic absorption band using the pyridinium-N-phenoxide betaine dye (Dimroth and Reichardt. The solubility also decreases with an increase in the length of the carbon chain for the ketones (acetone. Grant and Higuchi. Solubility. These differences may be due to the purity of the paracetamol and/or the solvents used. CS. 1990).g. The results on the solubility in water (0-30 °C) are in good agreement with data reported by Grant et al. 1985) d ln asolid S ) ∆H f + tp ∫ T Ttp (Cp. (1992) (CS ) 166. ].Journal of Chemical and Engineering Data. Reichardt. Solubility.. (1996) (CS ) 187. are higher than the values reported by Romero et al. 1-propanol. equilibrated crystals (from the solubility determinations) and the original crystals (the pharmaceutical material) were found to give identical X-ray powder diffraction patterns and identical behavior under DSC (i. ethanol. 1999 1393 Figure 1. Solubility. and hence the fugacity in the two phases is equal. whereas in dimethyl sulfoxide. water. The figure shows that PA has a very low solubility (<1 g of paracetamol/kg of solvent) in nonpolar hydrocarbons (toluene) and chlorinated hydrocarbons (carbon tetrachloride). CS.4). e. 1984). Activity Coefficients In a saturated solution.. showing no polymorphic changes. No. Two polymorphic forms of paracetamol are generally mentioned in the literature: a monoclinic form. 44. melting points and enthalpies of fusion).Cp. is given as g of PA/kg of solvent (solute-free basis) and represents the average of n samples from the same solution. 1984). and N. The solubility of paracetamol in n-alcohols decreases monotonically with a decrease in polarity or. diethylamine. 1968). i.g. In Figure 1 the solubility at 30 °C (Table 1) is plotted versus solvent polarity. 1996). acetone. 2. [.. Paracetamol is more soluble in ethanol than in ethanediol. 4.s) dT 2 RT dT - V l .s ) ∆Cp). and an orthorhombic form (with melting points about 157 °C) (Di Martino et al. (1996) (CS ) 12. is often assumed to be relatively insensitive to temperature (Walas.6). ×.4) is lower than the value reported by Romero et al. for each mean value is also reported.Cp. (1984) and Romero et al. +. of paracetamol versus temperature in b. The orthorhombic undergoes an endothermic transition to the monoclinic form at about 87 °C (Grant et al. whereas the solubility in ethyl acetate (CS ) 9. the solubility is >1000 g of paracetamol/kg of solvent. The solubility of PA in the isomers 1-propanol and 2-propanol differs only slightly. T Figure 3.. The solubility. Usually the last term on the right-hand side. with an increase in the length of the carbon chain. of paracetamol at 30 °C in n-alcohols versus the number of carbon atoms. the solubility versus the polarity parameter becomes a straight line for the homologous n-alcohols. which is above the range of temperatures used in the present work. and 4-methyl-2-pentanone). 0.l and the heat capacity of the crystalline form Cp. The corresponding standard deviation.N-dimethylformamide. In fact. Vol. in ethanol at 25 °C (CS ) 209.s. from 370 g in methanol down to 28 g/kg of solvent in 1-octanol.

and Vl . using indium as the calorimetric standard. . Reichardt. This explains the much lower ideal solubilities that are reported by Barra et al. as in water. The ideal solubility S of paracetamol. Paracetamol and citric acid in individual solvents.. Burger (1982). P. Pharm..1394 Journal of Chemical and Engineering Data. (1997). +. 1996. b. Ohm and Lippold (1982)). If the ideal solubility is compared with our measured solubilities. P. for example. Ideal Solubility. No. 4. J..5 if the Hildebrand approximation is used. 1-20. acetone.e. (1992). Lescure. of Paracetamol between -5 S and +30 °C Calculated from Eq 3 (with γS ) 1) t [°C] -5 0 5 10 xi [mole fraction] S 0. for example. present work. we derive: xSγS ) asolid ) S exp [ ∆Cp Tm T m ∆H f 1 m 1 +1 ln R Tm T R T T ( ) ( )] (3) where the subscript m designates the atmospheric melting point. (1996). The contribution from the heat capacity term in eq 3 is often assumed to be minor and is neglected (Walas. P. (1997). and with the approximations described above. For PA these two approximations are not justified in the temperature range of the present study. Acknowledgment The authors gratefully acknowledge the financial support of The Industrial Association for Crystallization Research and Technology (IKF) and The Swedish National Board for Industrial and Technical Development (NUTEK). Neau et al.. The enthalpy of fusion was determined by a PerkinElmer DSC-7 differential scanning calorimeter. 1984). Drache. F. 1985) even though it has been reported that this can lead to significant errors (Snow et al. The mean value and the standard deviation of six measurements are (27. Acta Pharm. the ideal solubility becomes lower by a factor of 2. Subrahmanyam et al.. 1968. The low activity coefficient in methanol.5) K of solid PA. and Manzo et al. Fairbrother (1974). Enthalpy of fusion (∆H f ) at the melting point (Tm) of m solid paracetamol determined by differential scanning calorimetry (×. Neau et al. Neau et al.-M. 49. Conflant. diethylamine.7 if the heat capacity term is completely neglected and becomes lower by a factor of 1. Technol. (1997) in eq 3.0690 0. K. J. Because the ideal solubility only depends on temperature. (1984).Vs is the difference in specific volumes of the condensed phases. 44.2) kJ mol-1 at the melting point (Tm): (443. xi . +. Activity coefficients. Literature Cited Barra. M. ]. 0. is given in Table 5. methanol. depending on the purity of the paracetamol) in the literature from about 26 kJ mol-1 (Manzo and Ahamuda. ×. 4.g. is negligible. but the aromatic ring and the methyl group influence the structure of the surrounding water molecules to such an extent that the net result becomes a low solubility. ethyl acetate. 1990. 1-8. and Astra Production Chemicals AB for providing the paracetamol used.0751 0. relates to the high solubility and reflects that the entropy effects are much weaker in methanol. 1-butanol. 2. (1997) determined experimentally ∆Cp at the melting point for paracetamol to be (99. Grant and Higuchi. Hildebrand et al. (1996).0584 0. and N. Pharm. Losungsmittel und Empirische Parameter ¨ zur Charakterisierung ihrer Polaritat. Dimroth.0497 0. we may estimate the activity coefficient of the solute in the saturated solutions. 1-propanol.... γS ) 1). Romero et al. Int. Curr. 644651. 2. (1990).0891 Figure 5. 128. Guyot-Hermann. of paracetamol versus temperature in b.0818 0. 1997. Burger.8 ( 2. J.. A. 1982. The alcohol group and the amide group are polar and may form hydrogen bonds to water. 1996) to 30. Results are given in Table 1 at 30 °C and at various temperatures in Figure 5. ¨ 1-73. the enthalpy of fusion varies (e. 0. between -5 and +30 °C.6 ( 0. Table 5. The solubility (xS) expressed as the mole fraction of PA is related to the activity of the solute in the saturated solution by the corresponding activity coefficient (γS). 28 (1). Bustamente.. which becomes 61. Guyot. and reflects that as a whole the paracetamol molecule is not very comfortable in the water environment. Doelker. The experimental solubility is lower than the ideal solubility in all solvents except for dimethyl sulfoxide. [. Zur Interpretation von Polymorphie-Untersuchungen.. acetonitrile. Chem. the estimated activity coefficient becomes inversely proportional to the measured solubility when different solvents are compared at equal temperatures. Grant et al. E. 1999 Figure 4. Vol. 1985). γS.-C.0635 t [°C] 15 20 25 30 xi [mole fraction] S 0.2 kJ mol-1 (Grant et al. Romero et al.N-dimethylformamide. O. 1990. 1986. Romero et al. A high activity coefficient value relates to a low solubility. As shown in Figure 4. The activity coefficient decreases with increasing temperature in all solvents.1 J mol-1 K-1 m m for PA using our own data. J. water. and often the triple point is very close to the atmospheric melting point (Walas. A new pure paracetamol for direct compression: the orthorhombic form.8) J mol-1 K-1. 9.. Top.. Di Martino. 11. By insertion of our measured enthalpy of fusion and melting point temperature and the heat capacity difference value of Neau et al. 6. ethanol. (1970) suggested that ∆Cp could be approximated with the entropy of fusion (∆S f ) ∆H f /Tm ≈ ∆Cp). C. Pharmacol. 1997). The expanded Hansen approach to solubility parameters.0538 0. 2-propanol. Manzo and Ahamuda (1990). At 30 °C. O. A. we may estimate the ideal solubility (xi ) of PA (i.1 ( 0.

E. Goates. 1984. In Solubility Behavior of Organic Compounds. J. E. and (cyclohexane + n-hexadecane) at 293. V: Enthalpic and entropic contributions to the free energy changes of disubstituted benzene derivatives in ethanol:water and ethanol: cyclohexane mixtures. Prausnitz. W.-L.15. Solvents and solvent effects in organic chemistry. Mehdizadeh. Manzo. 1997. Manuf.15 K. K. J. R. 1999 1395 Fairbrother. Florey. 18. 25-38. Ohm.. Pharm. R. Chow. Pharm. H. Regular and related solutions. P. 1970. J. Vol. Pharm.. Saunders. J. Int. A.. Grant. Chem. (Solid + liquid) and (vapor + liquid) phase equilibria and excess enthalpies for (benzene + n-tetradecane). J. H. Nonlinear van’t Hoff solubility-temperature plots and their pharmaceutical interpretation. J. M.. Bhandarkar. T... Pharm. H. Solubility of acetaminophen in cosolvents. Wiley-Interscience: New York. W. Pharm. B. C. S. 1061-1064. 78. Ed. Chem.. M. 107-130. J. Sci. Academic Press: New York. 1990. N. 44 (5). 601-605. O’Shea.. D. pp 5-29. K. S. Walas. H.. 298. Germany. Res. Scott. 1999. D. A. J. Nagai. T. JE990124V . (benzene + nhexadecane). Hildebrand. A. J. S. 340-343. Fairbrother. Bustamante. 32 (1). A. Marsh. In Analytical profiles of drug substances. 1984. S. Gundu Rao. DC. Reillo. Chem. 1990. Lippold... Snow. Phase Equilibria in Chemical Engineering. Effects of solvent medium on solubility.. Prod. 1109-1115. J.. 1996. 1992. J. W. Subrahmanyam. 21. H. 44. Bull. Ahumada. 3. Relationship of solubility curves to specific and nonspecific interactions. 1990. Technol. 1999. Received for review May 5. Int... R. S. Comparison of GE m calculated from (vapor + liquid) and (Solid + liquid) and equilibria. Differential molar heat capacities to test ideal solubility estimations. V. (cyclohexane + n-tetradecane).Journal of Chemical and Engineering Data. Series Ed.. M. S. J. J. Thermodyn. Irregular solution behaviour of paracetamol in binary solvents.. 1974. R. No. 1985. Stokes. S. Pharm..15 and 308. V. Ott.. 79 (12). 1986. Sreenivasa Reddy. B. W. Surface tension of solid drugs and its correlation with solubility. A.. B.. Hellmuth. E. L. M. Jr. Butterworth Publishers: Washington. Reichardt. Neau.. L. The behavior of paracetamol in mixtures of amphiprotic and amphiprotic-aprotic solvents. 17-24. Van Nostrand Reinhold Company: New York. Accepted August 31. 1-6. Bull. Romero.. VCH Verlagsgesellschaft: Weinheim.. H. Venkata Rao. Vol. 2nd ed. Prakongpan. C. J... Grant. Pharm. 6. Escalera. 1985.. 14 (5). P. 18. 6 (4). Int. Techniques of Chemistry Vol. Higuchi. R.. C. Acetaminophen.

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