Reactive Extraction of Penicillin III: Kinetics

The Chemical Engineering

Journal, 29 (1984)

B25

B25 - B29

Reactive Extraction of Penicillin III : Kinetics M. RESCHKE and K. SCHOGERL Institut fiir Technische

Chemie, Universitiit Hannover, Callinstrasse 3, D-3000 Hannover (F.R.G.)

(Received December 30,1983)

ABSTRACT

The kinetics of the reactive extraction and re-ex traction of penicillin G with Amberlite LA-2, dioctylamine and/or trioctylamine as carriers in n-butyl acetate, isobutyl acetate and/or chloroform as solvents were investiga ted in a stirred cell extractor. A kinetics model was developed, and the model parameters were identified using the measured data.

1. INTRODUCTION

In Part I [l] relationships were developed for the equilibrium constants, the distribution constants and the degrees of extraction of penicillins with amines as carriers as functions of the most important process parameters. In Part II [2] these constants were measured for penicillin G with various primary, secondary and tertiary amines as well as with quaternary ammonium salts. Also, penicillin V and the precursors phenylacetic acid and phenoxyacetic acid were extracted by this method. The investigations showed that secondary amines, especially Amberlite LA-2, are well suited to recover penicillin G and penicillin V from the fermentation medium. The aim here is to develop models for the extraction kinetics and to identify the model parameters by means of measured kinetics data.

2. KINETICS MODEL

The two-film model is used to describe the mass transfer across the liquid interface (Fig. 1) [3]. During physical extraction, only the free penicillin acid is extracted and for 0300-9467/84/$3.00

cA

cH%

&

CAHp

Tq

CHPorg

aqueous phase

inter-

organic phase

face

Fig. 1. Diagrammatic representation of the concentration profiles during the extraction of penicillin.

transfer across the interface the following balances hold: I’HP aq = kHp ag (CHP ag -

(la)

CHP WI, i )

in the aqueous phase and I’HP erg = bp

&CHP

org. i -

(lb)

CHP erg)’

in the organic solvent phase. The flux j is controlled by the mass transfer coefficients kHP aq and kHp ,,rg and the driving forces, i.e. the difference between the solute concentrations cnp aq in the bulk and cnp aq. i at the interface for the aqueous phase and the difference between the solute concentrations cnp ,,rg,i at the interface and cnp Orgin the bulk for the organic solvent phase. For the steady state (jnpaq = J’nporg) the inter-facial concentrations can be eliminated, i.e. k HP a&HP CHPaq,i

=

Ck HP

aq + bp erg + bp

or&HP

erg

(2)

aq

@ Elsevier Sequoia/Printed in The Netherlands

B26

where C = cnP,,rg,i/cnPaq, i i.5 the p&itiOIl coefficient. Hence, the extraction rate with regard to the penicillin concentration in the aqueous phase is as follows: -

dc HPaq -

(3)

k HPaqaP(CHPaq-CHPaq.i)

=

dt

where up is the specific interfacial area. When we substitute eqn. (2) in eqn. (3) we obtain -

dc HP ~

aq

k HPaqaPtCHPaq-

=

dt

k HP

-

aqCHP aq + bzp

Ck

or&HP

3. KINETICS

erg

CATION

(4)

jP=kP(+---c,,i)

(5)

for the penicillin, -CA,i)

(6)

for the amine and jAHP

= kAHp(CAHp,

i -

(7)

CAHP)

for the complex. The following relationships are valid in the same way as they are for the physical extraction: .iP = .iA = jAHP

KG =

CAHP,

i (9)

of these various equations

kA

kA’% k AHPKGCH

II2

+ k,c,,p kp&

cu

yields

+

kAnP&Cn

+

AND IDENTIFI-

The kinetics measurements were carried out in a stirred cell (Fig. 2) which was thermostatted at 20 “C. 150 ml of each of the organic and aqueous phases were placed in contact. The two impellers allowed separate mixing of the two phases without disturbance of the interface. The measurements were carried out with solutions of penicillin G in a potassium salt. The aqueous phase was recirculated through the cuvette of a polarimeter, and the penicillin G concentration was measured continuously over 3 - 4 h. During this time the decomposition of penicillin G remained below 5%. The stirrer speed was 150 rev min- ’ during the measurements. Most measurements were carried out with penicillin G and Amberlite LA-2 in n-butyl acetate. In Figs. 3 and 4 the relative concentrations of penicillin G with respect to their initial concentrations are plotted as a function of

(8)

cHcP,icA,i

Combination

MEASUREMENTS

OF MODEL PARAMETERS

HP erg + kHp aq

The kinetics of the reactive extraction of penicillin are described analogously when the following assumptions are made: the reaction plane is at the interface; the complex formation is an instantaneous reaction; no proton gradient exists in the aqueous phase. For the other components the following balance equations hold:

jA = k,(c,

Solutions to eqn. (10) were obtained by numerical integration. The same model can be used for the description of the dissociation of the amine-penicillin complex. Similar models were developed for the reactive extraction of HCl with Amberlite LA-2 [4 - 71 on the assumption that the reaction at the interface is instantaneous, i.e. the reaction rate is controlled by the rate of transfer of the components to the interface.

i

1

(10)

Fig. 2. Stirred

cell extractor.

B27

1.

to 0.293 cm-‘. This procedure yielded the following coefficients:

0

kp = 4.5 X 10e4 cm s-l

CP/CP(O)

k, = 1.0 x 1O-3 0.

s

Cm

S-l

k AHP= 6.5 X 1O-4 cm s-l

L 3.

0 t

0

[hl

Fig. 3. Dimensionless penicillin concentration in the aqueous phase as a function of the extraction time at pH 5 for various amine concentrations showing the calculated; 0, A, 0, extraction kinetics ( -, measured) of penicillin G in an (Amberlite LA-2)(n-butyl acetate) system (T= 20 “C; cp(0) = 10 mmol 1-l): curve 1, q, cA = 50 mmol 1-r).

0

2.

1.0

0

3. t

PI

0

With these coefficients excellent agreement was achieved between the measured and the calculated curves (Figs. 3 and 4). The limits of the model are shown in Fig. 5, in which the course of extraction is plotted at a constant amine concentration for various penicillin concentrations. For a large excess of penicillin, neglect of the physical extraction yields a lower calculated extraction rate than that measured. The following conclusions can be drawn from a comparison between the calculated and the measured curves (cp/cp(0) uersus t, where ~~(0) is the initial concentration of the penicillin). An increase in the carrier concentration does not significantly influence the extraction at pH 5, since the rate of extraction is controlled by the transport of penicillin to the interface. At pH 6 the effect of the amine concentration on the rate of reaction is significant because of the shift in the distribution equilibrium with increasing amine concentration at that pH value and the reduction in the penicillin concentration at the interface.

Fig. 4. Dimensionless penicillin concentration in the aqueous phase as a function of the extraction time at pH 6 for various amine concentrations showing the extraction kinetics (, calculated; 0, A, 0, measured of penicillin G in an (Amberlite LA-2)-(nbutyl acetate) system (7’ = 20 “C; ~(0) = 10 mmol 1-l): curvel_’ 1, curvt; 0, c 2. mmol ‘00 Tmol l-‘; curve fy a9 CA = I

,

,

A = 50

mm01

1-

).

time for various Amberlite LA-2 concentrations at pH 5.0 and pH 6.0. The extraction is enhanced with increasing amine concentration. The theoretical curves (eqn. (10)) were fitted to the measurements by identification of the three mass transfer coefficients kA, kAHP and kp, where the ratio kA/kAHp was kept constant (3:2). This ratio was evaluated from the diffusion coefficients calculated according to Wilke and Chang [8]. The equilibrium constant KG of the complex formation was evaluated as 1.25 X lo8 l* mol-* [ 21; the specific interfacial area up amounted

0

1.

0

2.

3.

0 t

PI

Fig. 5. Dimensionless penicillin concentration in the aqueous phase as a function of the extraction time at pH 5 for various penicillin concentrations showing calculated; 0, V, 0, 0, the extraction kinetics ( -, measured) of penicillin G in an (Amberlite LA-2)-(nbutyl acetate) system (T = 20 T; cA = 20 mmol 1-l): curve 1, 0, cp = 10 mm01 1-l; curve 2, v, cp = 20 mm01 1-l; curve 3,0, cp = 40 mm01 1-l; curve 4,0, cp = 80 mm01 1-l).

m

B28

An increase in the penicillin concentration does not influence the extraction rate as long as an excess of amine is present. With penicillin in excess the extraction rate diminishes as a result of a reduction in the mass transfer driving force. The same model has been used for the description of the re-extraction of penicillin (Fig. 6). The excellent agreement between the calculated and the measured curves indicates that the model is suitable. The results indicate that, in the pH range 7.5 - 8.0 and probably above, the re-extraction rate is determined solely by the concentration of the complex.

1

41-01 0.

5

..__..__...__.._............

Plotting the ratio of the re-extracted penicillin concentration to the initial concentration of the amine as a function of time yields only one curve. This indicates that the decomposition of the complex is a unimolecular reaction. The influence of the amine concentration is slight as long as the equilibrium favours the free amine. Using the model the dimensionless concentration of penicillin is plotted (Fig. 7) as a function of the extraction time for three different carriers (trioctylamine, Amberlite LA-2 and dioctylamine) in isobutyl acetate at pH 5.0. Dioctylamine not only has the highest affinity for penicillin G [ 21 but also results in the highest extraction rate. The concentration 1.

r

CP/CP(( .._.................. j._..............._.......,

a.

-I

0 t 0

1. 0

2. 0

3. 0 t

culated;

0, 0, measured)

of penicillin

calG from an =

20 V, = 10 mmol 1-l; 0, pH 8.0, CA,G = 4.6 mmol I-‘, CAH~= 3.4 mmol 1-l; 0, pH 8.0, CA,G = 17.8 mmol I-‘, CAH~ = 14.6 mmol I-‘.

[hl

Fig. 8. Dimensionless penicillin concentration as a function of the extraction time showing the predicted extraction kinetics of penicillin G with Amberlite LA-2 and various organic solvents (T= 20 ‘C; pH 6.0; q(O) = 4 mmol 1-‘; CA = 20 mmd lmm’):curve 1, chloroform; curve 2, isobutyl acetate; curve 3, nbutyl acetate.

1.

CP/CPK 0.

3. 0 t [hl

Fig. 7. Dimensionless penicillin concentration in the aqueous phase as a function of the extraction time showing the predicted extraction kinetics of penicillin G with different carriers in isobutyl acetate (T= 20 “C; pH 5.0; ~~(0) = 4 mmol 1-l; CA = 20 mmol I-‘): curve 1, trioctylamine; curve 2, Amberlite LA-2; curve 3, dioctylamine.

3. 0 tlhl

Fig. 9. Dimensionless penicillin concentration as a function of the extraction time showing the predicted extraction kinetics of penicillin G with dioctylamine and various organic solvents (2’ = 20 “C; pH 6.0; cp(0) = 4 mm01 1-l; CA = 20 mmol 1-r): curve 1, chloroform; curve 2, isobutyl acetate; curve 3, nbutyl acetate.

B29

gradient of penicillin in the film on the aqueous side of the interface seems to control the process. In Figs. 8 and 9, again using the model, the influence of the organic solvent on the extraction is shown with Amberlite LA-2 and dioctylamine respectively as carriers. The highest rate is attained with n-butyl acetate and the lowest rate with chloroform. Isobutyl acetate yields a slightly lower rate than IIbutyl acetate. Higher extraction rates can be attained with dioctylamine than with Amberlite LA-2. More measurements are necessary to explain this behaviour.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the financial support of the Ministry of Research and Technology, F.R.G., and the support of Hoechst AG.

Sakai, The effect of chemical reaction on the rate of solvent extraction, Proc. Znt. Solvent Extraction Conf., 1971, Vol. 2, pp. 831 - 839. T. Tsuneyuki, K. Kondo, Y. Kawano and F. Nakashio, Solvent extraction of hydrochloric acid by long chain alkylamine in a stirred transfer cell, J. Chem. Eng. Jpn., 11 (3) (1978) 198 - 202. T. Kataoka, T. Nishiki and K. Ueyama, Mass transfer with liquid anion exchange, Chem. Eng. J., 10 (1975) 189 - 195. T. Kataoka, T. Nishiki and K. Ueyama, Simultaneous mass transfer of acid and ions in a liquid anion exchanger, Chem. Eng. J., 12 (1976) 233 237. C. R. Wilke and P. Chang, Correlation of diffusion coefficients in dilute solutions, AZChE J., I (1955) 264 - 270.

APPENDIX A: NOMENCLATURE ap

c c i

k

REFERENCES M. Reschke and K. Schiigerl, Reactive extraction of penicillin, I, Stability of penicillin G in the presence of carriers and relationships for distribution coefficients and degrees of extraction, Chem. Eng. J., 28 (1984) Bl - B9. M. Reschke and K. Schiigerl, Reactive extraction of penicillin, II, Distribution coefficients and degrees of extraction, Chem. Eng. J., 28 (1984) Bll - B20. M. Reschke, Reaktivextraktion von penicillin, Doctoral Thesis, University of Hannover, 1983. F. Nakashio, T. Tsuneyuki, K. Inone and W.

KCi t T

specific interfacial area (cm-‘) concentration (mol 1-i or mm01 1-l) partition coefficient mass flux (mol cm-* s-l) mass transfer coefficient (cm s-i) equilibrium constant (l* mol-*) time (min) temperature (“C)

Subscripts aqueous phase aq A amine, carrier AHP amine-penicillin complex H proton HP penicillin acid i interface organic phase org P penicillin