Thermochemical investigation of theophylline, theophylline hydrate and their aqueous solutions

Thermochemical investigation of theophylline, theophylline hydrate and their aqueous solutions

31 Thermochimica Acta, ‘72 (1984) 31-40 Elsevier Science Publishers B.V., Amsterdam -Printed in The Netherlands THERMOCHEMICAL THEOPHYLLINE SABINE ...

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31

Thermochimica Acta, ‘72 (1984) 31-40 Elsevier Science Publishers B.V., Amsterdam -Printed in The Netherlands

THERMOCHEMICAL THEOPHYLLINE SABINE

INVESTIGATION HYDRATE

BRUNS,

Institut D-3300

AND THEIR

JOACHIM

REICHELT

fiir Physikalische

Technische

OF THEOPHYLLINE,

Universitat,

Braunschweig

AQUEOUS

SOLUTIONS

and HEIKO

K. CAMMENGA

und Theoretische

Hans-Sommer-Str.

Chemie,

10,

(F.R.Germany)

ABSTRACT Theophylline, although structurally very similar to caffeine, does not exhibit a solid state phase transition. In contrast to of which the quadruple point and caffeine, it forms a monohydrate, enthalpy of hydration have been determined. Furthermore, solubility and enthalpy of solution measurements are discussed. INTRODUCTION Purines

are widespread

animal.and caffeine, Fig.

human

metabolism.

theophylline

l.Theophylline,

in green

tea, mate

decaffeination of asthma

in nature

the subject and other

and cardial

similarities

7-methyl

derivative

paper,

occurs

inter alia

drug

differences

in the

in the treatment

is used as a diuretic.

as distinct

in

important,

and may be a by-product

It is an important and

role

dioxo-purines

are the most

of this

plants

diseases with

an important

Of the methylated

and theobromine

of coffee.

as well

and play

from

It shows

its

caffeine.

MATERIALS At 60°C,

a saturated

solution

ticals,

Inc.)

in dist.

yielded

fine,

long needles

fuging

solution 99,98

for several

weeks

of Na2C03, 10 H20

anhydrous mol-%.

of theophylline which

was prepared,

of theophylline

the rest of adhering

hydrate gave

water

solution

was

hydrate. removed

at 92 % rel. humidity ("conditioning").

theophylline.

The purity

(ICN Pharmaceuon slow cooling After

centri-

by storing over

Desiccation

was determined

the

a saturated at 9D°C by DSC as

32 THEOPHYLLINE

HYDRATE

Composition In the

literature

and pharmacopoe,

are both

reported

observed

that caffeine

decided

to check

Both

isothermal

that

theophylline

indeed

also

in fact forms

hydrate

(if conditioned

are in accord

analyses,

see Fig. 2 (ref. 2, 3, 4).

Stability

point point,

often

is the temperature

point,

dynamically

stable

and vapour

pressure.

discrepancies. solution HIGUCHI

Literature

a,

(ref. 6). ABOU-SHAABAN

curves

obtain

undertaken

powder

mined

X-ray

the stability

encapsulated hydrate

(s) -+

followed

by DSC at various

extrapolated heating

crucibles (s)

temperature

rate.

67 . ..68"C

of peak

can be deduced.

measurements:

Samples

sealed

crucibles,

periods

of 6... 13 days

the dehydration nPD first

in

168 h at 66°C as a sample

peak resp.

held

value

were held showed

steps,

hydrate

deterwas

(1)

Fig. 3 shows with

a value

was checked hydrate,

of

to about

decreasing aD

=

in

herme-

temperatures

analysed

for

by DSC whether

that

the-hydrate

the

by isothermal

up or not. Having

166 h at 66.9"C

that

enclosed

at constant

it was observed

189 h at 67'C

pressure

(1)

decreases

rate,

and subsequently

still

greater

Theophylline

onset

of theophylline

tically

et al. have

(ref. 8). We have

rates.

heating

This

=

from TG and DTG

sat. soln.

+

and

3,

and the reaction

heating

For vanishing

solution

rate of

and REIER

DSC and vapour

in two ways.

anhydrate

is thermo-

SHEFTER

(ref. 7). FOKKENS

~9'~ = 63.8+1.3'C

in hermetic

structural

resp.

and theophylline

diffraction,

point

is

and

of its own saturated

and SIMONELLI

52...8O"C

and report

above)

to as the quadruple

a hydrate

(ref. 5) and WADKE

73.6"C

a range

the X-ray

of solubility

hydrate

= 73OC

showed

data of "rD show considerable

From measurements

deduce

with

l), we

hydrate.

however,

as described

referred

in the presence

(ref.

theophylline.H20

J'D up to which

of theophylline

measurements

also

and caffeine

we had previously

of theophylline

TG measurements,

The compositions

H20 found

The stability

Since

a 4/5-hydrate

the composition

and dynamic

a monohydrate.

caffeine-O.8

theophylline

to form monohydrates.

approached

after

tempering

was stable,

99 % had converted.

where

33

II

I

IV

Caffeine

Theophylline

Paraxanthine

Theobromine

I1.3,7-Trimethyl-

l1,3-Dimethyl-

l1.7-Dimethyl-

(3,7-Dimethyl-

xonthine

1.

Fig.

Ill

Structural

1

1

xonthine

formulae

of

xonthine

some

1

methyl-substituted

xonthine

I

xanthines.

I’

NY-

N

W’

_.

H+-01, ‘\ ‘. flO\H_. --N

N____ H-4;:;

, N.‘-

_“-A

‘\ ROXH. .H “.N

H./ ‘.

2.0x

-\ P-H_,*

N_‘-

w

.H -g:”

.H

‘N N.--

Caffeine

Hydrate

_ H--O\” “;o.T

-.

N

“+H_. #’

‘.

‘\ IO‘“. -. H ‘N #’ -a .HMo\ H N’-‘. ‘. /O‘H. -. H ‘N .’ ,’ 2.76x _ H/O8 H\ N”‘\ ‘. /O-H. ,H -‘.N /’ 2.m 1 _n--0,” N-‘/ ‘\ ‘. /O‘n. H %N ,/ N.”

‘L PLH_ H

-H/Ox”

“N

.H 4;

““N

‘. .’

‘lo’“, H

Theophylline

%N

Hydrate

Fig. 2. The hydrogen bonding in the crystal structures of caffeine hydrate and theophylline hydrate. Projection on the (001) plane (ref. 2, 3, 4).

34 We thus

conclude

Fig. 3 shows hydrates curve

that 2,

of theophylline

for caffeine

not approach

point

heating

as determined

by isothermal

A?'D = 51.5"C.

BOTHE

shown

by DSC,

diffraction

calorimetry besides

that

to the p-form.

This

be careful

Thus

CES\ARO and STAREC hydrate,

results

This example

in deducing

DSC measurements

Enthalpy

obviously

which

solid

report A?,

which

of caffeine

= 86OC

fraction

in a kinetic

hindrance

again

that one temperatures

the heating

rate.

for the stability

is 35°C too high

of

recon-

transition

varied

and

subsequently

shows

state

even when having

long-

and CAMMENGA

a considerable

is formed,

reaction.

from

the dehydration

p-caffeine

d-polymorph

of the dehydration

of caffeine

during

the stable

X-ray

Jo-

rate by far does

yield

the metastable

(ref.

point

12)!

of dehydration

The enthalpy of ~10

of dehydration

mg at a heating

capsules.

The data observed

vapour

(ref.

1). For the enthalpy

10.5tO.3

formation

hydrogen

bonding

theophylline

whereas

compared hydrate

for sat.

samples

in caffeine

continuous

hydrate

from

whereas

are

stronger

lattice

hydrate,

chains

the chains

a hydrate,

=

is 50 % higher

is expected

in the crystal

to that

and

previously

we obtain AH; 1, this

sealed

solution

as described

value

molecules shows

in caffeine

does not form

has to be investigated ANHYDROUS

A higher

of the water

hydrate

Theobromine

corrected

the capsule

of dehydration

hydrate.

Fig. 2. Theophylline molecules

were

within

As is seen from Table

kJ*mol-'.

for caffeine

was determined by DSC with -1 in hermetically

rate of 2 Kwmin

water

than

It is seen that the

for vanishing

the stability

rate for the

which

solution

should

on the heating

1, 9, 10, 11) have

hydrate verts

of JD

and caffeine.

hydrate

time measurements, (ref.

= 67.0'0.2°C.

the dependence

of

see

of bound

water

interrupted.

paraxanthine

still

in detail.

THEOPHYLLINE

Polymorphism Caffeine 140... 141°C siderations inter alia

shows

order

have predicted in caffeine

to have found 260°C,

a first

(ref. 9). GRABOWSKA

phase

transition

at

from

structural

con-

and KALISZAN

polymorphism

and theophylline

some evidence

when theophylline

polymorphic

in a number (ref.

for a polymorphic

was obtained

of purines,

13). DOSER

believed

transition

near

by desiccation

of its hydrate

35

0

lg (hebting rate IK min”)

Fig. 3. Extrapolated temperatures of the onset of the dehydration peak [DSC curve) as a function of the heating rate, under which the measurements had been made.

-6

-7

-6 2.7E-03

2.9E-03

3.1E-03

3.3E-03

3. SE-03 T-’

Fig.

4.

water. HIGUCHI work.

/

K-’

Solubility of theophylline hydrate and theophylline in 0 data of FOKKENS (ref. 8, 15); n data of SHEFTER and (ref. 5); X scattered literature data;0 data of this

36

TABLE

1

Comparison

of some thermochemical

The enthalpy

of solution

Property

Phase

data

data of important

are given

Theophyll ine

transition

AHi/kJ.mol-'

in

purines.

kJ-mol-’

Caffeine

141°C

(DSC)

140°C

(TMA)

'heobromine

4.1

Melting

point

271.2"C

236.1"C

348.5"C

4Hi/kJ

mol-'

30.9

21.6

(13.1)

Thermal

stabi lity

(DSC)

Hydrate

(TG)

Quadruple AHi/kJ

poi nt

mol-'

Solubility per

in mol

medium

very good

- 1 H20

- 0.8 H20

67°C

51.5"C

10.5

7.06

3.72.10-2

poor

1.092.10-'

1000 g of water

at 25OC

Anhydrate 401

,

401,

298

c-0,

c s’

19.83

in

298

prep.

16.32

in

prep.

in prep.

in prep.

36.7

in prep.

23.38

in prep.

Hydrate 30.6

&H&8

401

, c-0,

298+ AH;

30.3

37

(ref.

14). FOKKENS

et al. report

(ref. 8, 15). We, however, phase

transition

hydrate other

neither

crystailisation

of the melt

from

resulted

uncertain

no evidence

in theophylline:

nor fast

quenching

another

found

observation‘

for a polymorphic

quick

dehydration

non-aqueous

in a sample

of the

solvents

showing

or

thermal

events

than melting.

Fusion Melting fusion

of theophylline

is 30.921.0

occurs

kJ.mol-';

at 271.5'0.5"C.

this

is about

The enthalpy

40 % higher

than

of

for

caffeine. Thermal

stability

The thermal in food

stability,

technology,

-in the absence

of oxygen-

crucibles

or sealed

mally

1 h at various

for

and analysed stability creases

in the order

it occured

from

kJ
quickly

The thermal

and markedly

de-

which

the

ideal

of solution

= 18.6 kJ-mol-'3

from

15).

of solution"

that aqueous 11). This

interactions,

equation

of caffeine

see Table

(ref.

between

Since one knows activity coefficient AH ”

hydrate (ref. 8,

gave no evidence

an "enthalpy

however,

("base-stacking").

the

of his data

he deduced

being

sandwiching

of pH=5

an equation

and solute/solute

ing in molecular

of theophylline

(2)

We had found,

are far from

solvent/solute

enthalpy

isother-

theobromine.

solutions

a plot

he fitted

to all his data,

centration,

were

aluminium

were held

analysis.

compounds

>theophylline>

buffer

to him that

point,

t const.

that

inter alia

samples

then cooled

DSC purity

the solubility

in aqueous

In XC = - &_. R. T

ments

These

temperatures,

for organic

Pure

in hermetic

ampoules.

fixed

caffeine

has measured

of a quadruple

solutions

importance

SOLUTIONS

and theophylline

of 43.1

encapsulated

into glass

is astonishing

FOKKENS

is of great

been determined.

by computer-assisted

THEOPHYLLINE

Since

which

has also

the

caffeine

is due to latter

two or more purine

from osmotic is a strong

coefficient function

(2) is far from

hydrate

1. Furthermore,

AHi

the

result-

molecules

measurecon-

of last

c ,2g8

equatton

(2)

is

only

a

38 very' rough fitting

equation

for solubility

solutions,

e.g. when the measurement

As we have

shown

for

e.g.

In x can often

in t/T (ref.

equation

AH;;8

In x for the solubility fitted

by polynomials

hydrate close

measurements

point

of solution

better

(Fig. 5) If

(ref. 8, 15) is

in l/T for theophylline

the curves

of,$,,

fit

power

is calculated.

of FOKKENS

power

Fig. 4.

of second

true for theophylline

= 30.6 kJ*mol-'

separately,

to the stability

a much

with a polynomial

of second

and anhydrate

The enthalpy

is not good,

in the case of caffeine,

be obtained

11). The same proved

and from this

data of non-ideal

accuracy

= 67°C

at infinite

intersect

as found

dilution

at 66'C,

by us, fig. 6.

for the hydrates

is

, c-0,

AH8O1

One obtains kJ.mol-'

298 +

AH;. for theophylline

30.3 kJ.mol-'

for caffeine

of theophylline

hydrate.

higher must

in theophylline solubility

thus

Such

must

be much

its high temperature to better

and HIGUCHI

from

their partition

16), which

they defend by NMR

structure/interaction are the subject

increment)

with

against

(ref.

The much of caffeine

of caffeine

conclusions

coefficient

drawn measure-

controversial

but

17).

relationships

of further

inter-

smaller.

"base-stacking"

is in accord

re-sults obtained

solutions

and 23.38

AH;;8 in the case

to

that the solute/solute

This

(ref.

doubtful

means

solutions

in solution.

by GUTTMAN ments

(and

be attributed

molecules

hydrate

is close

(30.6 kJemo1 -') but far from the value for caffe-

ine (36.7 kJ.mol-') , which actions

This

studies

in purine under

way

and other in our

laboratory. ACKNOWLEDGEMENTS We thank

Oeutsche

Forschungsgemeinschaft,

and Fends

der Chemischen

financial

support.

Industrie,

Frankfurt

Bonn-Bad am Main,

Godesberg, for

39

-5

c x 2 -6

-7

AE-03

3.1E-03

3.3E-03

3.SE-03 T-’

Fig.

5.

Solubility been by a polynomial

The data have

as

/

K-’

of theophylline hydrate of this work alone. fitted as well by equation (2) (dotted line) of second power in l/T (full line).

Fig. 6. In this figure the solubility data of FOKKENS (ref. have been fitted for theophylline hydrate and theophylline rately by polynomials of second power in l/T. The intersection at 66”C, see text.

8, 15) sepais

REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

H. Bothe and H. K. Cammenga, Thermochim. Acta 40 (1980) 29-39 D. J. Sutor, Acta Crystallogr. 11 (1958) 83-87 D. J. Sutor, Acta Crystallogr. 11 (1958) 453-458 R. Gerdil and R. E.Marsh, Acta Crystallogr. 12 (1960) 166-167 E. Shefter and T. Higuchi, J. Pharm. Sci. 52 (1963) 781-791 D. A. Wadke and G. E. Reier, J. Pharm. Sci. 61 (1973) 868-871 R. R. A. Abou-Shaaban and A. P. Simonelli. Thermochim. Acta 26 (1978) III-124 J. G. Fokkens, J. G. M. van Amelsfoort, C. J. de Blaey, C. G. de Kruif and J. Wilting, 3. Pharm. - in press H. Bothe and H. K. Cammenga, J. Thermal Anal. 16 (1979) 267-275 H. Bothe and H. K. Cammenga, Proc. IX Int. Coll. on Coffee ASIC, London, 1980, Vol. 1, p. 135-144 H. Bothe and H. K. Cammenga, Thermochim. Acta - in press A. Cesdro and G. Starec, J. Phys. Chem. 84 (1980) 1345-1346 I. Grabowska and R. Kaliszan, Acta Polon. Pharm. 29 (1972) 537-538 H. Doser, Arch. Pharm. (1943) 251-256 3. G. Fokkens, PhD Thesis, Univ. of Utrecht, The Netherlands, 1983 D. Guttman and T. Higuchi, J. Pharm. Sci. 60 (1971) 1269-1270 A. L. Thakkar, L. G. Tensmeyer and W.L. Wilham, J. Pharm. Sci. 60 (1971) 1267-1269