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Interaction between naproxen and chemically modified β-cyclodextrins in the liquid and solid state
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ELSEVIER
European Journal of Pharmaceutical Sciences 3 (1995) 347-355
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Interaction between naproxen and chemically modified 13-cyclodextrins in the liquid and solid state Paola Mura a'*, Giampiero Bettinetti b, Fabrizio Melani a, Alfredo Manderioli a ~Dipartimento di Scienze Farmaceutiche, Universitg~ di Firenze, Via G. Capponi 9, 1-50121 FI, Italy bDipartimento di Chimica Farmaceutica, Universitg~ di Pavia, Viale Tararnelli 12, 1-27100 PV, Italy
Received 11 December 1994; accepted 19 May 1995
Abstract
The complexation between naproxen and some chemically modified /3-cyclodextrins (hydroxyethyl /3-cyclodextrin with average substitution degree per anhydroglucose unit 0.6, 1.0 and 1.6; hydroxyproyl fl-cyclodextrin with average substitution degree per anhydroglucose unit 0.6 and 0.9) was studied using phase-solubility analysis and molecular modelling. The amorphous carriers exhibit similar solubilizing effects and complexing abilities, which are reflected by a comparable increase in drug dissolution rate to about the same extent from equimolar blends with each chemically modified /3-cyclodextrin. X-ray diffractometry and differential scanning calorimetry data indicate a role of the degree of substitution of the carrier in the decrease in crystallinity of naproxen in equimolar blends with chemically modified fl-cyclodextrins. Naproxen; Hydroxyethyl /3-cyclodextrin; Hydroxyproyl /3-cyclodextrin; Phase-solubility analysis; Molecular modelling; X-ray diffractometry; Differential scanning calorimetry; Thermogravimetric analysis Keywords:
1. Introduction
Naproxen ((S)-(+)-6-methoxy-a-methyl-2-naphthaleneacetic acid, NAP) is a non-steroidal anti-inflammatory drug whose very low water solubility (about 27 mg L -1 at 25°C) is improved by complexation with both native and chemically modified cyclodextrins (Bettinetti et al., 1989, 1990). Since the nature of the substituent and the degree of substitution of a cyclodextrin derivative may play a role in this performance (Bettinetti et al., 1992), the solubilizing capacity toward NAP of hydroxyethyl fl-cyclodextrin (HEflCd) with an average substitution degree per anhydroglucose unit (MS) of 0.6, 1.0 and 1.6, and of hydroxypropyl fl-cyclodextrin (HPflCd) with MS 0.6 and *Corresponding author. Tel. (+39-55) 275 7292; Fax (+39-55) 240 776. 0928-0987/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved S S D I 0928-0987(95)00025-9
0.9 was investigated. Phase-solubility analysis at different temperatures and the molecular modelling approach were the methods used to investigate the interaction of NAP with these /3Cd derivatives and to complement previous C-13 NMR results on NAP-HP/3CD MS 0.9 and NAPHE/3CD MS 1.6 systems (Bettinetti et al., 1991). In the study of NAP-cyclodextrin inclusion complexation, phase-solubility analysis was complemented by computer-aided molecular modelling. The effect of the solubility enhancement on drug dissolution rate was determined by testing physical mixtures of NAP and each /3-cyclodextrin derivative in the 1:1 (mol/mol) ratio according to the dispersed amount and rotating disc methods. X-ray diffractometry (powder method) and differential scanning calorimetry (DSC) were used to check and evaluate the crystallinity of NAP in equimolar physical mixtures with chemi-
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P. Mura et al. / European Journal of Pharmaceutical Sciences 3 (1995) 347-355
cally modified /3-cyclodextrins and to demonstrate possible drug-carrier interactions in the solid state.
2. Experimental procedures Materials. Naproxen (NAP) (Sigma Chemical Co, St. Louis, MO, USA), hydroxyethyl /3cyclodextrin (HE/3Cd) with an average substitution degree per anhydroglucose unit (MS) of 0.6, 1.0 and 1.6 (donated by Wacker-Chemie GmbH, Munich, Germany) and hydroxypropyl /3cyclodextrin (HPflCd) with MS 0.6 and 0.9 (donated by Wacker-Chemie GmbH, Munich, Germany) were used as received. Water contents of amorphous /3-cyclodextrin derivatives (determined by thermogravimetric analysis) ranged from 6% to 7% (as mass fraction). All other materials and solvents were of analytical reagent grade. Surface area determination. Surface area determinations were performed with a surface area analyser Flowsorb II 2003 (Micromeritics, Georgia, USA) following the BET single point method (Brunauer et al., 1938). Samples were outgassed under a flux of argon/nitrogen 7/3 mixture at 70°C for 4 h, and the surface area was determined by measuring the volume of nitrogen absorbed by the sample kept in liquid nitrogen. Preparation of NAP/[3-cyclodextrin derivatii~e systems. Physical mixtures in the drug to carrier 1:1 (mol/mol) ratio were prepared by gently and smoothly blending in an agate mortar w i t h a pestle NAP (75-150 /zm sieve granulometric fraction) and the /3-cyclodextrin derivative (75150/zm sieve granulometric fraction). Solubility studies. Solubility measurements of NAP were carried out by adding 30 mg of drug to 30 mL of water or aqueous solution of /3cyclodextrin derivative in the 5-100 mmol L -I concentration range, in a sealed glass container which was electromagnetically stirred at a constant temperature (25, 37 or 45°C) until equilibrium was achieved. An aliquot was withdrawn and filtered (pore size 0.45 mm), and the NAP
concentration was determined by a second derivative ultraviolet absorption method at 274 nm (Bettinetti et al., 1989). Each experiment was performed in triplicate.
Dissolution studies. Dissolution rates of NAP from physical mixtures of the drug (75-150 /xm sieve granulometric fraction) with each /3cyclodextrin derivative (75-150 /zm sieve granulometric fraction) in the equimolar ratio, as well as those of the drug alone and colyophilized with an equimolar amount of native/3-cyclodextrin (/3Cd), were determined in water at 37-+ 0.3°C according to the dispersed amount and rotating disc methods. Dispersed amount experiments were performed under non-sink conditions, by adding 100 mg of NAP or NAP equivalent to 300 mL of water, in a 400 mL beaker. A glass three-blade propeller (19 mm diameter) was immersed in the beaker at 25 mm from the bottom and rotated ( f = 100 min-1). Suitable aliquots were withdrawn with a filter-syringe (pore size 0.45 /xm) at the specified times and assayed for NAP content as in the solubility studies. The same volume of fresh medium was added to the beaker and the correction for the cumulative dilution was calculated. Each test was repeated four times (coefficient of variation CV < 1.4%). In the rotating disc method, samples of 300 mg were compressed using a hydraulic press at a force of about 2 t (disc area 1.33 cmZ). Tablets were inserted into a stainless steel holder, so that Only one face was exposed to dissolution medium (150 mL). The holder, attached to a metal shaft, was then connected to a stirring motor, immersed in a 200 mL beaker and rotated ( f = 100 min-t). At appropriate interval times, samples of dissolution medium were withdrawn and spectrophotometrically assayed for NAP content as above. Sink-conditions were maintained almost throughout the whole experiment; in fact the drug concentration at the end of the experiment never exceeded 20% of its saturation solubility. Each test was repeated four times (coefficient of variation CV < 8%). Molecular modelling. Analysis and modelling of the structures of the HE/3Cd-NAP, HP/3Cd-NAP, and/3Cd-NAP complexes were carried out using the INSIGHT 2.2.0 program (Biosym Tech-
P. Mura et al. / European Journal of Pharmaceutical Sciences 3 (I995) 347-355
nologies, San Diego, CA, USA). The /3cyclodextrin derivatives were built up by adding 4 (MS 0.6), 6 (MS 0.9), 7 (MS 1.0) or 11 (MS 1.6) hydroxyalkyl groups to /3Cd as a base molecule. Six patterns of substituent distribution were examined for the tetra-substituted fl-cyclodextrins, and three for the hexa-, epta- and the undecasubstituted ones, respectively. N A P was fitted into the cavity in an axial orientation, with the carboxyl group directed toward the widest rim of the cavity (Bettinetti et al., 1991). Each structure was subjected to a process of energy minimization ( C V F F force field, D I S C O V E R 2.9 program, Biosym Technologies), performing iterations to a <0.05 derivative value. Molecular dynamic simulations were performed at 27°C (time step 1 fs, equilibrium time 100 fs, step n u m b e r 10000). Docking energies were calculated at both - 2 7 3 ° C (rigid molecule) and 27°C, averaging in the last case the energies of 51 conformations generated during the dynamic molecular program (5-10 ps).
Thermal analysis.
T e m p e r a t u r e and enthalpy m e a s u r e m e n t s were performed with a Mettler TA4000 apparatus equipped with a DSC 25 cell (5 or 10 K min -1) on 5-10 mg (Mettler M3 microbalance) samples in pierced AI pans under static air. Thermogravimetric analysis (TGA) was conducted on a Mettler T G 50 apparatus (5 or 10 K min -~) on 15-25 mg samples in alumina crucibles under a nitrogen atmosphere (10 m L / rain).
349
HE/3Cd MS 1.6 is d e p e n d e n t on the formation of an inclusion complex with the respective /3Cd derivative (Bettinetti et al., 1991). In the presence of HP/3Cd MS 0.6 and HE/3Cd MS 0.6 and 1.0, the N A P solubility linearly increased following the A L type phase-solubility diagram (Fig. la). The relative increase in the presence of 100 mmol L -~ of e a c h / 3 C d derivative at 25°C, 37°C, and 45°C was more p r o n o u n c e d at the lowest temperature (Fig. lb). The increase resulted 200times the N A P solubility for the HP/3CD MS 0.9 derivative and somewhat less for the other cyclodextrins. The thermodynamic parameters obtained from the temperature d e p e n d e n c y of the apparent 1:1 stability constants of the inclusion complexes within the 25-45°C temperature range are shown in Table 1, with those of the NAP-/3Cd inclusion complex (Bettinetti et al., 1989) for coNparison.
2O o E E
15
10 D. ,< Z
5
U
•
0
|
-
20
i
40
-
i
60
!
80
•
1
100
c(Cd), mmot/L (b) 200"1
2soc
[ HPI3Cd ~ ; ~
HESCd
37=C
X-ray analysis. X-ray diffraction patterns were collected with a computer-controlled Philips PW 1800 apparatus in the 2-40 ° 20 interval (scan rate 1° m i n - l ) , using a C u K a radiation monochromatized with a graphite crystal. Spectra of NAP-cyclodextrin blends were recorded at room t e m p e r a t u r e on both freshly prepared samples and after heating at 1 5 0 - 3 ° C in an oven for 15 rain. 3. Results and discussion
3.1. Interaction in aqueous solution We have already shown that the solubilisation of N A P p r o m o t e d by HPflCd MS 0.9 and
~
MS 0.6
1
1.6
0.6
4Soc
0.9
Fig. 1. (a) Phase solubility diagrams in aqueous solution at 25°C of naproxen (NAP) with hydroxyethyl fl-cyclodextrin (HE/3Cd) MS 0.6 (e) and 1.0 (O), and with hydroxypropyl /3-cyclodextrin (HP/3Cd) MS 0.6 ([2). (b) Relative increase in aqueous solubility of NAP in the presence of 100 mmol L -~ HEflCd MS 0.6, 1.0, and 1.6 or HP/3Cd MS 0.6 and 0.9 at 25, 37, and 45°C, as a function of the average substitution degree (MS).
350
P. Mura et al. / European Journal of Pharmaceutical Sciences" 3 (1995) 347-355
Table 1 Stability constants and derived thermodynamic parameters for the interaction of naproxen (NAP) with fl-cyclodextrin (/SCd), hydroxyethyl/3-cyclodextrin (HE/SCd) MS 0.6, 1.0 and 1.6, and hydroxypropyl /3-cyclodextrin (HP/SCd) MS 0.6 and 0.9 in unbuffered aqueous solution (pH ~ 5) Cyclodextrin
Apparent stability constant K~1:~) (L mol -z)
AG~5oc (kJ mol -~)
AH ° (kJ mol -~)
/xS°5.c (J mol -~ K-~)
25°C
32°C
37°C
45°C
~Cd
1702
1482
1388
-
-18.5
-13.2
17.6
H E ~ C d 0.6 H E ~ C d 1.0 H E ~ C d 1.6 HP~Cd 0.6 HP~Cd 0.9
2337 2175 2145 2083 2580
-
1716 1745 1800 1726 1976
1539 1358 1729 1694 1464
-19.2 -19.0 -19.0 -18.9 -19.4
-16.8 -18.2 -8.7 -12.0 -17.1
8.1 2.8 34.5 23.1 8.2
The inclusion behaviour of NAP with the /3Cd derivatives tested was not influenced by the substitution degree as concerns stoichiometry, thermodynamic, and basic complexation mechanism.
3.2. Molecular modelling Computer-generated structures of NAPHE/SCd inclusion complexes are shown in Fig. 2. Van der Waals energy values of docking between some/3-cyclodextrins (host) and NAP (substrate) at - 2 7 3 and 27°C are shown in Table 2. Patterns
(a), (b), and (c) for derivatives with MS 0.6 were selected according to the preferential distribution of four substituents on a /SCd molecule (Irie et al., 1988). No statistically significant differences in docking energy values were observed when varying the relative position of substituted glucoses within either pattern (a) (e.g., 1-2-4-6 or 1-3-5-7) or pattern (b) (e.g., 1-2 or 1-4) of the derivatives with MS 0.6. The same holds for HE/SCd MS 1.0 and HP/SCd MS 0.9 when one or two substituents were moved from the primary to a secondary OH group on the same glucose ring within the respective pattern (a), and also for
Table 2 Docking energies for the interaction of naproxen (NAP) with fl-cyclodextrin (/SCd), some hydroxyethyl /3-cyclodextrin derivatives (HE/3Cd MS 0.6, 1.0 and 1.6), and some hydroxypropyl fl-cyclodextrin derivatives (HP/3Cd MS 0.6 and 0.9) at - 2 7 3 and 27°C (standard deviation for values at 27°C in parentheses) Cyclodextrin
/SCd HE/SCd 0.6 HEflCd 0.6 HE/SCd 0.6 HE/SCd 1.0 HE/3 Cd 1.6 HP/SCd 0.6 HP/SCd 0.6 HP/SCd 0.6 HP/3Cd 0.9 (a) (b) (c) (d)
Substituent per/SCd mole
Distribution of substituents
-
(a) (b) (c) (a) (d) (a) (b) (c) (a)
4 4 4 7 11 4 4 4 6
Docking energy ( k J m o l - t ) -273°C
27°C
-149 - 173 -177 - 174 - 181 - 185 - 182 - 164 - 159 - 192
- 1 4 0 (8) - 153 (8) -145 (7) - 152 (7) - 157 (9) - 162 (9) - 150 (8) - 143 (9) - 152 (6) - 154 (8)
Substituents at the level of primary OH groups distributed equally between the glucoses. Three substituents clustered on one glucose, the fourth on a primary OH group. Substituents forming on oligomeric chain on a primary OH group. Seven substituents on primary O H groups, four distributed equally between the glucoses.
P. Mura et al.
European Journal of Pharmaceutical Sciences 3 (1995) 347-355
351
(lb)
Fig. 2. Computer-generated 1:1 (mol/mol) inclusion complexes between naproxen (NAP) and hydroxyethyl /3-cyclodextrin (HE/3Cd) with different average substitution degree (MS). (1) MS 0.6: (a) four substituents on primary OH groups of glucoses 1, 3, 5, 7; (b) three substituents on the OH groups of glucose 1, the fourth on the primary OH group of glucose 4; (2) MS 1.0: seven substituents on primary OH groups. (3) MS 1.6: seven substituents on primary OH groups, four at the level of O(2)H secondary groups of glucoses 1, 3 and O(3)H of glucoses 5, 7.
H E / 3 C d MS 1.6 w h e n the relative position of glucoses substituted at the level of secondary O H groups within pattern (d) was varied (e.g., 1-2-5-6 or 1-3-5-7). As can be seen in Table 3, statistically significant differences (P < 0.05) were instead found b e t w e e n the docking energy values of the interactions of N A P with /3Cd and its hydroxyalkyl derivatives, except b e t w e e n patterns (a) and (c) of HE/3Cd MS 0.6.
3.3. Dissolution tests
The noticeable i m p r o v e m e n t in the properties of N A P dissolution from its e q u i m o l a r physical mixtures with all the /3-cyclodextrin derivatives tested (Fig. 3a) can be attributed to the inclusion complex formation as well as to an increase in drug wettability and a decrease in N A P crystallinity (see below). It should be highlighted that
352
P. Mura et al. / European Journal o f Pharmaceutical Sciences 3 (1995) 347-355
(a) 2
5
0
(b)
~
20
200 15o
10
o. ,¢ z
100 Cc
C
C
0
0
50 •
0
!
•
10
i
•
i
•
i
•
20 30 40 time (rain)
i
50
•
i
60
0 MS 0
0.6
1
1.6
0.6
0.9
Fig. 3. (a) Dissolution curves of naproxen (NAP) ( e ) , NAP/fl-cyclodextrin 1:1 (mol/mol) colyophilized product (©), and equimolecular physical mixtures of NAP with hydroxyethyl fl-cyclodextrin (HEflCd) with average substitution degree MS (fq) 0.6, (r-q) 1.0, (11) 1.6, and with hydroxypropyl/3-cyclodextrin (HP/3Cd) MS (111)0.6 and (&) 0.9 (dispersed amount method, four runs, coefficient of variation CV< 1.4%). (b) Ratios between the amount of NAP dissolved from NAP/cyclodextrin physical mixtures (A) and that from NAP alone (B) at t = 2 min (11) and 10 rain (EJ).
Table 3 Specific surface (S,) of naproxen (NAP), hydroxyethyl (HE/3Cd) and hydroxypropyl (HP/3Cd)/3-cyclodextrins with different average substitution degrees (MS) NAP MS S, (m2/g)
0.64
HEflCd 0.6 0.64
1.0 0.79
HPflCd 1.6 0.64
0.6 0.86
0.9 1.78
this improvement was also clearly higher than from the NAP/fl-cyclodextrin colyophilized product, which previously showed the best dissolution properties in comparison with the corresponding physical mixture, coground and coevaporated products (Bettinetti et al., 1989). A comprehensive picture of the relative increase in the initial amount of NAP dissolved in the dissolution (b)
(a) 150
30
[] k = lo.9 ~ , = d • k = lo.~ a k = 9.0
s ~.,~' .~'~.~
0 k= 2.5
.J
E 20
27%
-
~/If~
HPGCd
L._ /----
100'
::L
a.
10
z
~---~--.
0
,=
.
;,
100 200 time (s)
;.
300
0 MSO
0.6
1
1.6
0.6
0.9
Fig. 4. (a) Dissolution rate of naproxen (NAP) ( e ) , NAP//3-cyclodextrin 1:1 (mol/mol) colyophilized product (©), and equimolecular physical mixtures of NAP with hydroxyethyl/3-cyclodextrin (HE/3Cd) with average substitution degree MS (11) 0.6, (I-q) 1.0, ([]) 1.6, and with hydroxypropyl fl-cyclodextrin (HP/3Cd) MS (A) 0.6 and (D) 0.9 (rotating disc method, four runs, coefficient of variation C V < 8 % ) . (b) Ratios between the dissolution rate of NAP from NAP/cyclodextrin physical mixtures (C) and that of NAP alone (D).
P. Mura et al. / European Journal of Pharmaceutical Sciences 3 (1995) 347-355
m e d i u m is given in Fig. 3b. Dissolution tests were also p e r f o r m e d on non-disintegrating tablets at constant surface area to avoid effects of particle size and hence specific surface area. The results showed a similar trend to the dispersed amount experiments (Fig. 4a). The improvement in N A P dissolution rate occurred to about t h e same extent for the various carriers tested. The N A P dissolution rate constants, calculated from the linear portion of dissolution profiles of compressed physical mixtures with /3-cyclodextrin derivatives, were on average 10 /xg cm -2, two order of magnitude higher than those of N A P alone (0.09/zg cm -2) and for times that of NAP13Cd colyophilized product (2.5 /xg cm-2). The
'"
-
L
50
.
.
.
.
1
....
I00
:
150
200
250
t.0_01 ~
300
*C
~r~
0.00
5,0
I
i 15.0
l
25~.0
2 "O
Fig. 5. DSC (5 K min -1) and TGA (5 K rnin -~, dashed line) curves of naproxen (NAP) and hydroxypropy113-cyclodextrin (HP/3Cd) with average substitution degree (MS) 0.6, and X-ray powder diffraction patterns of hydroxypropyl /3-cyclodextrin MS 0.6 (a), HEI3Cd MS 0.6 (b), 1.0 (c), 1.6 (d), and NAP (e).
353
relative increase in N A P dissolution rate is shown in Fig. 4b.
3.4. Interaction in solid state
Thermal behaviour and X-ray powder diffraction patterns of N A P and /3-cyclodextrin derivatives indicated the crystalline, anhydrous state of the drug and the amorphous, hydrate nature of the carrier (Fig. 5). Noticeable exothermal effects associated with weight loss were displayed by the derivatives at the lowest substitution degree (MS) in the 215-240°C temperature range. In the case of HP/3Cd MS 0.6 the exotherm peaked at 231°C, with an enthalpy change of 13.5 J g - i (Fig. 5). Comparing the X-ray diffraction and DSC data in Fig. 6 with those for N A P alone (Fig. 5), it is evident that the crystallinity of N A P decreased in equimolar physical mixtures with the a m o r p h o u s 13-cyclodextrin derivatives, and disappeared in the case of NAPHP/3Cd MS 0.9 system when the mixture was kept in an oven for 15 min at 150 + 3°C, a few degrees below the melting point of NAP. DSC analysis allowed us to evaluate the decrease in crystallinity of N A P (AfH= 135 J g - t , mp 156.2°C (Bettinetti et al., 1991b)) through the determination of its specific fusion enthalpy in physical mixtures with /3-cyclodextrin derivatives (values on DSC curves in Fig. 6). The results showed that about 24%, 50% and 80% (as mass fraction) of N A P were brought to an a m o r p h o u s state in equimolar physical mixtures with HE/3Cd MS 0.6, 1.0 and 1.6, respectively. HP/3Cd MS 0.6 was twice as active as HE/3Cd at the same MS (50% compared to 24% N A P amorphized under the same experimental conditions), whilst HP/3Cd MS 0.9 showed the most powerful amorphizing capacity toward NAP. The specific surface area of the carrier (Table 3) seems not to play a role in the solid state interaction between N A P and HE/3Cd, since the derivatives which display the highest and the lowest amorphizing capacity (i.e. HE/3Cd MS 0.6 and 1.6) have the same S w. A contribution of this parameter to the analogous interaction with HP/3Cd can not be ruled out because the m o r e active derivative (MS 0.9) has a surface area
P Mura et al. / European Journal o f Pharmaceutical Sciences 3 (1995) 347-355
354
r.t,
r . t .
156"c
I
5.1
I
/
I
l
15.0
I
25.0 29 jg-I
150"C
20
5.0
I
'
'
I
15.0
I
25.0
~0
c
143"C 50 i00 Temperature,
150 "C
50 i00 150 Temperature, "C
Fig. 6. X-ray powder diffraction patterns (samples at room temperature (r.t.) and kept at 150°C for 15 rain in an oven (150°C)) and DSC curves (10 K min -l) of equimolecular physical mixtures of naproxen (NAP) with hydroxyethyl fl-cyclodextrin (HE/3Cd) with average substitution degree (MS) 0.6 (a), 1.0 (b), 1.6 (c), and with hydroxypropyl fl-cyclodextrin (HPflCd) MS 0.6 (d) and 0.9 (e).
which is twice that of the less reactive one (MS 0.6).
4. Conclusions T h e HE/3Cds and HP/3Cds tested exhibit a similar solubilizing effect (on average 185 times the a q u e o u s solubility, in 0.1 M solution of /3-
cyclodextrin derivative at 25°C) and complexing ability (stability constants about 2300 L mo1-1 at 25°C, docking energy about - 1 5 0 kJ mol -t at 27°C, as from Tables 1 and 2) toward NAP. This is reflected by the i m p r o v e m e n t in the dissolution properties of N A P physically mixed with these a m o r p h o u s carriers, which is m u c h m o r e pron o u n c e d than that o b t a i n e d using the a m o r p h o u s colyophilized p r o d u c t of N A P with native /3-
P. Mura et al. / European Journal o f Pharmaceutical Sciences 3 (1995) 347-355
cyclodextrin. In fact, on the basis of X-ray diffraction and DSC data, a carrier-induced amorphization process of NAP occurs in physical mixtures with both HE/3Cds and HP,BCds. It can be ascribed to a loosening of crystal forces of the drug dispersed within the amorphous carrier phase and seems to be related to the nature of the substituent (HP/3Cd > HE/3Cd) and to MS of the carrier (HE/3Cd MS 1.6 > HE/3Cd MS 1.0 > HE/3Cd MS 0.6; HP]3Cd MS 0.9 > HP/3Cd MS 0.6). Using the molecular modelling procedure it is possible to predict conformation and interaction energy of/3Cd complexes of which crystal structure can not be determined. Docking energy values (Table 2), calculated for some patterns of substituent distribution on a 13Cd molecule, obviously do not reflect the actual situation of random substitution. Nevertheless, these data indicate a more stable inclusion complexation of N A P with chemically modified ]3-cyclodextrins than with native ]3Cd, in agreement with the thermodynamic parameters obtained from solubility studies.
Acknowledgements Financial support from the MURST (60%) and CNR is gratefully acknowledged.
355
References Bettinetti, G.P., Mura, P., Liguori, A. and Bramanti, G. (1989) Solubilization and interaction of naproxen with cyclodextrins in aqueous solution and in the solid state. Farmaco 2, 195-213. Bettinetti, G.P., Mura, P., Melani, F., Giordano, F. and Setti, M. (1990) (S)-(+)-6-methoxy-a-methyl-2-naphthaleneacetic acid and/3-cyclodextrin derivatives: inclusion in aqueous media and solid phase interaction. Minutes, 5th Int. Symp. Cyclodextrins, edited by D. Duchgene. Ed. de Sant~, Paris, pp. 239-242. Bettinetti, G.P., Melani, F., Mura, P., Monnanni, R. and Giordano, F. (1991a) Carbon-13 NMR study of naproxen interaction with cyclodextrins in solution. J. Pharm. Sci. 80, 1162-1170. Bettinetti, G.P., Mura, P., Giordano, F. and Setti, M. (1991b) Thermal behaviour and physicochemical properties of naproxen in mixtures with polyvinylpirrolydone. Thermochim. Acta 199, 165-171. Bettinetti, G.P., Gazzaniga, A., Mura, P., Giordano, F. and Setti, M. (1992) Thermal behaviour and dissolution properties of naproxen in combinations with chemically modified /3-cyclodextrins. Drug Dev. Ind. Pharm. 18, 39-53. Brunauer, S., Emmett, T.H. and Teller, E. (1938) Adsorption of gases in multimolecular layers. J. Am. Chem. Soc. 60, 309-319. Irie, T., Fukunaga, K., Yoshida, A. Uekama, K., Fales, H.M. and Pitha, J. (1988) Amorphous water-soluble cyclodextrin derivatives: 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisobutyl, and carboxamidomethyl derivatives of 13-cyclodextrin. Pharm. Res. 5, 713-717.
ELSEVIER
European Journal of Pharmaceutical Sciences 3 (1995) 347-355
JOURNAL
OF
PHARMACEUTICAL SCIENCES
Interaction between naproxen and chemically modified 13-cyclodextrins in the liquid and solid state Paola Mura a'*, Giampiero Bettinetti b, Fabrizio Melani a, Alfredo Manderioli a ~Dipartimento di Scienze Farmaceutiche, Universitg~ di Firenze, Via G. Capponi 9, 1-50121 FI, Italy bDipartimento di Chimica Farmaceutica, Universitg~ di Pavia, Viale Tararnelli 12, 1-27100 PV, Italy
Received 11 December 1994; accepted 19 May 1995
Abstract
The complexation between naproxen and some chemically modified /3-cyclodextrins (hydroxyethyl /3-cyclodextrin with average substitution degree per anhydroglucose unit 0.6, 1.0 and 1.6; hydroxyproyl fl-cyclodextrin with average substitution degree per anhydroglucose unit 0.6 and 0.9) was studied using phase-solubility analysis and molecular modelling. The amorphous carriers exhibit similar solubilizing effects and complexing abilities, which are reflected by a comparable increase in drug dissolution rate to about the same extent from equimolar blends with each chemically modified /3-cyclodextrin. X-ray diffractometry and differential scanning calorimetry data indicate a role of the degree of substitution of the carrier in the decrease in crystallinity of naproxen in equimolar blends with chemically modified fl-cyclodextrins. Naproxen; Hydroxyethyl /3-cyclodextrin; Hydroxyproyl /3-cyclodextrin; Phase-solubility analysis; Molecular modelling; X-ray diffractometry; Differential scanning calorimetry; Thermogravimetric analysis Keywords:
1. Introduction
Naproxen ((S)-(+)-6-methoxy-a-methyl-2-naphthaleneacetic acid, NAP) is a non-steroidal anti-inflammatory drug whose very low water solubility (about 27 mg L -1 at 25°C) is improved by complexation with both native and chemically modified cyclodextrins (Bettinetti et al., 1989, 1990). Since the nature of the substituent and the degree of substitution of a cyclodextrin derivative may play a role in this performance (Bettinetti et al., 1992), the solubilizing capacity toward NAP of hydroxyethyl fl-cyclodextrin (HEflCd) with an average substitution degree per anhydroglucose unit (MS) of 0.6, 1.0 and 1.6, and of hydroxypropyl fl-cyclodextrin (HPflCd) with MS 0.6 and *Corresponding author. Tel. (+39-55) 275 7292; Fax (+39-55) 240 776. 0928-0987/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved S S D I 0928-0987(95)00025-9
0.9 was investigated. Phase-solubility analysis at different temperatures and the molecular modelling approach were the methods used to investigate the interaction of NAP with these /3Cd derivatives and to complement previous C-13 NMR results on NAP-HP/3CD MS 0.9 and NAPHE/3CD MS 1.6 systems (Bettinetti et al., 1991). In the study of NAP-cyclodextrin inclusion complexation, phase-solubility analysis was complemented by computer-aided molecular modelling. The effect of the solubility enhancement on drug dissolution rate was determined by testing physical mixtures of NAP and each /3-cyclodextrin derivative in the 1:1 (mol/mol) ratio according to the dispersed amount and rotating disc methods. X-ray diffractometry (powder method) and differential scanning calorimetry (DSC) were used to check and evaluate the crystallinity of NAP in equimolar physical mixtures with chemi-
348
P. Mura et al. / European Journal of Pharmaceutical Sciences 3 (1995) 347-355
cally modified /3-cyclodextrins and to demonstrate possible drug-carrier interactions in the solid state.
2. Experimental procedures Materials. Naproxen (NAP) (Sigma Chemical Co, St. Louis, MO, USA), hydroxyethyl /3cyclodextrin (HE/3Cd) with an average substitution degree per anhydroglucose unit (MS) of 0.6, 1.0 and 1.6 (donated by Wacker-Chemie GmbH, Munich, Germany) and hydroxypropyl /3cyclodextrin (HPflCd) with MS 0.6 and 0.9 (donated by Wacker-Chemie GmbH, Munich, Germany) were used as received. Water contents of amorphous /3-cyclodextrin derivatives (determined by thermogravimetric analysis) ranged from 6% to 7% (as mass fraction). All other materials and solvents were of analytical reagent grade. Surface area determination. Surface area determinations were performed with a surface area analyser Flowsorb II 2003 (Micromeritics, Georgia, USA) following the BET single point method (Brunauer et al., 1938). Samples were outgassed under a flux of argon/nitrogen 7/3 mixture at 70°C for 4 h, and the surface area was determined by measuring the volume of nitrogen absorbed by the sample kept in liquid nitrogen. Preparation of NAP/[3-cyclodextrin derivatii~e systems. Physical mixtures in the drug to carrier 1:1 (mol/mol) ratio were prepared by gently and smoothly blending in an agate mortar w i t h a pestle NAP (75-150 /zm sieve granulometric fraction) and the /3-cyclodextrin derivative (75150/zm sieve granulometric fraction). Solubility studies. Solubility measurements of NAP were carried out by adding 30 mg of drug to 30 mL of water or aqueous solution of /3cyclodextrin derivative in the 5-100 mmol L -I concentration range, in a sealed glass container which was electromagnetically stirred at a constant temperature (25, 37 or 45°C) until equilibrium was achieved. An aliquot was withdrawn and filtered (pore size 0.45 mm), and the NAP
concentration was determined by a second derivative ultraviolet absorption method at 274 nm (Bettinetti et al., 1989). Each experiment was performed in triplicate.
Dissolution studies. Dissolution rates of NAP from physical mixtures of the drug (75-150 /xm sieve granulometric fraction) with each /3cyclodextrin derivative (75-150 /zm sieve granulometric fraction) in the equimolar ratio, as well as those of the drug alone and colyophilized with an equimolar amount of native/3-cyclodextrin (/3Cd), were determined in water at 37-+ 0.3°C according to the dispersed amount and rotating disc methods. Dispersed amount experiments were performed under non-sink conditions, by adding 100 mg of NAP or NAP equivalent to 300 mL of water, in a 400 mL beaker. A glass three-blade propeller (19 mm diameter) was immersed in the beaker at 25 mm from the bottom and rotated ( f = 100 min-1). Suitable aliquots were withdrawn with a filter-syringe (pore size 0.45 /xm) at the specified times and assayed for NAP content as in the solubility studies. The same volume of fresh medium was added to the beaker and the correction for the cumulative dilution was calculated. Each test was repeated four times (coefficient of variation CV < 1.4%). In the rotating disc method, samples of 300 mg were compressed using a hydraulic press at a force of about 2 t (disc area 1.33 cmZ). Tablets were inserted into a stainless steel holder, so that Only one face was exposed to dissolution medium (150 mL). The holder, attached to a metal shaft, was then connected to a stirring motor, immersed in a 200 mL beaker and rotated ( f = 100 min-t). At appropriate interval times, samples of dissolution medium were withdrawn and spectrophotometrically assayed for NAP content as above. Sink-conditions were maintained almost throughout the whole experiment; in fact the drug concentration at the end of the experiment never exceeded 20% of its saturation solubility. Each test was repeated four times (coefficient of variation CV < 8%). Molecular modelling. Analysis and modelling of the structures of the HE/3Cd-NAP, HP/3Cd-NAP, and/3Cd-NAP complexes were carried out using the INSIGHT 2.2.0 program (Biosym Tech-
P. Mura et al. / European Journal of Pharmaceutical Sciences 3 (I995) 347-355
nologies, San Diego, CA, USA). The /3cyclodextrin derivatives were built up by adding 4 (MS 0.6), 6 (MS 0.9), 7 (MS 1.0) or 11 (MS 1.6) hydroxyalkyl groups to /3Cd as a base molecule. Six patterns of substituent distribution were examined for the tetra-substituted fl-cyclodextrins, and three for the hexa-, epta- and the undecasubstituted ones, respectively. N A P was fitted into the cavity in an axial orientation, with the carboxyl group directed toward the widest rim of the cavity (Bettinetti et al., 1991). Each structure was subjected to a process of energy minimization ( C V F F force field, D I S C O V E R 2.9 program, Biosym Technologies), performing iterations to a <0.05 derivative value. Molecular dynamic simulations were performed at 27°C (time step 1 fs, equilibrium time 100 fs, step n u m b e r 10000). Docking energies were calculated at both - 2 7 3 ° C (rigid molecule) and 27°C, averaging in the last case the energies of 51 conformations generated during the dynamic molecular program (5-10 ps).
Thermal analysis.
T e m p e r a t u r e and enthalpy m e a s u r e m e n t s were performed with a Mettler TA4000 apparatus equipped with a DSC 25 cell (5 or 10 K min -1) on 5-10 mg (Mettler M3 microbalance) samples in pierced AI pans under static air. Thermogravimetric analysis (TGA) was conducted on a Mettler T G 50 apparatus (5 or 10 K min -~) on 15-25 mg samples in alumina crucibles under a nitrogen atmosphere (10 m L / rain).
349
HE/3Cd MS 1.6 is d e p e n d e n t on the formation of an inclusion complex with the respective /3Cd derivative (Bettinetti et al., 1991). In the presence of HP/3Cd MS 0.6 and HE/3Cd MS 0.6 and 1.0, the N A P solubility linearly increased following the A L type phase-solubility diagram (Fig. la). The relative increase in the presence of 100 mmol L -~ of e a c h / 3 C d derivative at 25°C, 37°C, and 45°C was more p r o n o u n c e d at the lowest temperature (Fig. lb). The increase resulted 200times the N A P solubility for the HP/3CD MS 0.9 derivative and somewhat less for the other cyclodextrins. The thermodynamic parameters obtained from the temperature d e p e n d e n c y of the apparent 1:1 stability constants of the inclusion complexes within the 25-45°C temperature range are shown in Table 1, with those of the NAP-/3Cd inclusion complex (Bettinetti et al., 1989) for coNparison.
2O o E E
15
10 D. ,< Z
5
U
•
0
|
-
20
i
40
-
i
60
!
80
•
1
100
c(Cd), mmot/L (b) 200"1
2soc
[ HPI3Cd ~ ; ~
HESCd
37=C
X-ray analysis. X-ray diffraction patterns were collected with a computer-controlled Philips PW 1800 apparatus in the 2-40 ° 20 interval (scan rate 1° m i n - l ) , using a C u K a radiation monochromatized with a graphite crystal. Spectra of NAP-cyclodextrin blends were recorded at room t e m p e r a t u r e on both freshly prepared samples and after heating at 1 5 0 - 3 ° C in an oven for 15 rain. 3. Results and discussion
3.1. Interaction in aqueous solution We have already shown that the solubilisation of N A P p r o m o t e d by HPflCd MS 0.9 and
~
MS 0.6
1
1.6
0.6
4Soc
0.9
Fig. 1. (a) Phase solubility diagrams in aqueous solution at 25°C of naproxen (NAP) with hydroxyethyl fl-cyclodextrin (HE/3Cd) MS 0.6 (e) and 1.0 (O), and with hydroxypropyl /3-cyclodextrin (HP/3Cd) MS 0.6 ([2). (b) Relative increase in aqueous solubility of NAP in the presence of 100 mmol L -~ HEflCd MS 0.6, 1.0, and 1.6 or HP/3Cd MS 0.6 and 0.9 at 25, 37, and 45°C, as a function of the average substitution degree (MS).
350
P. Mura et al. / European Journal of Pharmaceutical Sciences" 3 (1995) 347-355
Table 1 Stability constants and derived thermodynamic parameters for the interaction of naproxen (NAP) with fl-cyclodextrin (/SCd), hydroxyethyl/3-cyclodextrin (HE/SCd) MS 0.6, 1.0 and 1.6, and hydroxypropyl /3-cyclodextrin (HP/SCd) MS 0.6 and 0.9 in unbuffered aqueous solution (pH ~ 5) Cyclodextrin
Apparent stability constant K~1:~) (L mol -z)
AG~5oc (kJ mol -~)
AH ° (kJ mol -~)
/xS°5.c (J mol -~ K-~)
25°C
32°C
37°C
45°C
~Cd
1702
1482
1388
-
-18.5
-13.2
17.6
H E ~ C d 0.6 H E ~ C d 1.0 H E ~ C d 1.6 HP~Cd 0.6 HP~Cd 0.9
2337 2175 2145 2083 2580
-
1716 1745 1800 1726 1976
1539 1358 1729 1694 1464
-19.2 -19.0 -19.0 -18.9 -19.4
-16.8 -18.2 -8.7 -12.0 -17.1
8.1 2.8 34.5 23.1 8.2
The inclusion behaviour of NAP with the /3Cd derivatives tested was not influenced by the substitution degree as concerns stoichiometry, thermodynamic, and basic complexation mechanism.
3.2. Molecular modelling Computer-generated structures of NAPHE/SCd inclusion complexes are shown in Fig. 2. Van der Waals energy values of docking between some/3-cyclodextrins (host) and NAP (substrate) at - 2 7 3 and 27°C are shown in Table 2. Patterns
(a), (b), and (c) for derivatives with MS 0.6 were selected according to the preferential distribution of four substituents on a /SCd molecule (Irie et al., 1988). No statistically significant differences in docking energy values were observed when varying the relative position of substituted glucoses within either pattern (a) (e.g., 1-2-4-6 or 1-3-5-7) or pattern (b) (e.g., 1-2 or 1-4) of the derivatives with MS 0.6. The same holds for HE/SCd MS 1.0 and HP/SCd MS 0.9 when one or two substituents were moved from the primary to a secondary OH group on the same glucose ring within the respective pattern (a), and also for
Table 2 Docking energies for the interaction of naproxen (NAP) with fl-cyclodextrin (/SCd), some hydroxyethyl /3-cyclodextrin derivatives (HE/3Cd MS 0.6, 1.0 and 1.6), and some hydroxypropyl fl-cyclodextrin derivatives (HP/3Cd MS 0.6 and 0.9) at - 2 7 3 and 27°C (standard deviation for values at 27°C in parentheses) Cyclodextrin
/SCd HE/SCd 0.6 HEflCd 0.6 HE/SCd 0.6 HE/SCd 1.0 HE/3 Cd 1.6 HP/SCd 0.6 HP/SCd 0.6 HP/SCd 0.6 HP/3Cd 0.9 (a) (b) (c) (d)
Substituent per/SCd mole
Distribution of substituents
-
(a) (b) (c) (a) (d) (a) (b) (c) (a)
4 4 4 7 11 4 4 4 6
Docking energy ( k J m o l - t ) -273°C
27°C
-149 - 173 -177 - 174 - 181 - 185 - 182 - 164 - 159 - 192
- 1 4 0 (8) - 153 (8) -145 (7) - 152 (7) - 157 (9) - 162 (9) - 150 (8) - 143 (9) - 152 (6) - 154 (8)
Substituents at the level of primary OH groups distributed equally between the glucoses. Three substituents clustered on one glucose, the fourth on a primary OH group. Substituents forming on oligomeric chain on a primary OH group. Seven substituents on primary O H groups, four distributed equally between the glucoses.
P. Mura et al.
European Journal of Pharmaceutical Sciences 3 (1995) 347-355
351
(lb)
Fig. 2. Computer-generated 1:1 (mol/mol) inclusion complexes between naproxen (NAP) and hydroxyethyl /3-cyclodextrin (HE/3Cd) with different average substitution degree (MS). (1) MS 0.6: (a) four substituents on primary OH groups of glucoses 1, 3, 5, 7; (b) three substituents on the OH groups of glucose 1, the fourth on the primary OH group of glucose 4; (2) MS 1.0: seven substituents on primary OH groups. (3) MS 1.6: seven substituents on primary OH groups, four at the level of O(2)H secondary groups of glucoses 1, 3 and O(3)H of glucoses 5, 7.
H E / 3 C d MS 1.6 w h e n the relative position of glucoses substituted at the level of secondary O H groups within pattern (d) was varied (e.g., 1-2-5-6 or 1-3-5-7). As can be seen in Table 3, statistically significant differences (P < 0.05) were instead found b e t w e e n the docking energy values of the interactions of N A P with /3Cd and its hydroxyalkyl derivatives, except b e t w e e n patterns (a) and (c) of HE/3Cd MS 0.6.
3.3. Dissolution tests
The noticeable i m p r o v e m e n t in the properties of N A P dissolution from its e q u i m o l a r physical mixtures with all the /3-cyclodextrin derivatives tested (Fig. 3a) can be attributed to the inclusion complex formation as well as to an increase in drug wettability and a decrease in N A P crystallinity (see below). It should be highlighted that
352
P. Mura et al. / European Journal o f Pharmaceutical Sciences 3 (1995) 347-355
(a) 2
5
0
(b)
~
20
200 15o
10
o. ,¢ z
100 Cc
C
C
0
0
50 •
0
!
•
10
i
•
i
•
i
•
20 30 40 time (rain)
i
50
•
i
60
0 MS 0
0.6
1
1.6
0.6
0.9
Fig. 3. (a) Dissolution curves of naproxen (NAP) ( e ) , NAP/fl-cyclodextrin 1:1 (mol/mol) colyophilized product (©), and equimolecular physical mixtures of NAP with hydroxyethyl fl-cyclodextrin (HEflCd) with average substitution degree MS (fq) 0.6, (r-q) 1.0, (11) 1.6, and with hydroxypropyl/3-cyclodextrin (HP/3Cd) MS (111)0.6 and (&) 0.9 (dispersed amount method, four runs, coefficient of variation CV< 1.4%). (b) Ratios between the amount of NAP dissolved from NAP/cyclodextrin physical mixtures (A) and that from NAP alone (B) at t = 2 min (11) and 10 rain (EJ).
Table 3 Specific surface (S,) of naproxen (NAP), hydroxyethyl (HE/3Cd) and hydroxypropyl (HP/3Cd)/3-cyclodextrins with different average substitution degrees (MS) NAP MS S, (m2/g)
0.64
HEflCd 0.6 0.64
1.0 0.79
HPflCd 1.6 0.64
0.6 0.86
0.9 1.78
this improvement was also clearly higher than from the NAP/fl-cyclodextrin colyophilized product, which previously showed the best dissolution properties in comparison with the corresponding physical mixture, coground and coevaporated products (Bettinetti et al., 1989). A comprehensive picture of the relative increase in the initial amount of NAP dissolved in the dissolution (b)
(a) 150
30
[] k = lo.9 ~ , = d • k = lo.~ a k = 9.0
s ~.,~' .~'~.~
0 k= 2.5
.J
E 20
27%
-
~/If~
HPGCd
L._ /----
100'
::L
a.
10
z
~---~--.
0
,=
.
;,
100 200 time (s)
;.
300
0 MSO
0.6
1
1.6
0.6
0.9
Fig. 4. (a) Dissolution rate of naproxen (NAP) ( e ) , NAP//3-cyclodextrin 1:1 (mol/mol) colyophilized product (©), and equimolecular physical mixtures of NAP with hydroxyethyl/3-cyclodextrin (HE/3Cd) with average substitution degree MS (11) 0.6, (I-q) 1.0, ([]) 1.6, and with hydroxypropyl fl-cyclodextrin (HP/3Cd) MS (A) 0.6 and (D) 0.9 (rotating disc method, four runs, coefficient of variation C V < 8 % ) . (b) Ratios between the dissolution rate of NAP from NAP/cyclodextrin physical mixtures (C) and that of NAP alone (D).
P. Mura et al. / European Journal of Pharmaceutical Sciences 3 (1995) 347-355
m e d i u m is given in Fig. 3b. Dissolution tests were also p e r f o r m e d on non-disintegrating tablets at constant surface area to avoid effects of particle size and hence specific surface area. The results showed a similar trend to the dispersed amount experiments (Fig. 4a). The improvement in N A P dissolution rate occurred to about t h e same extent for the various carriers tested. The N A P dissolution rate constants, calculated from the linear portion of dissolution profiles of compressed physical mixtures with /3-cyclodextrin derivatives, were on average 10 /xg cm -2, two order of magnitude higher than those of N A P alone (0.09/zg cm -2) and for times that of NAP13Cd colyophilized product (2.5 /xg cm-2). The
'"
-
L
50
.
.
.
.
1
....
I00
:
150
200
250
t.0_01 ~
300
*C
~r~
0.00
5,0
I
i 15.0
l
25~.0
2 "O
Fig. 5. DSC (5 K min -1) and TGA (5 K rnin -~, dashed line) curves of naproxen (NAP) and hydroxypropy113-cyclodextrin (HP/3Cd) with average substitution degree (MS) 0.6, and X-ray powder diffraction patterns of hydroxypropyl /3-cyclodextrin MS 0.6 (a), HEI3Cd MS 0.6 (b), 1.0 (c), 1.6 (d), and NAP (e).
353
relative increase in N A P dissolution rate is shown in Fig. 4b.
3.4. Interaction in solid state
Thermal behaviour and X-ray powder diffraction patterns of N A P and /3-cyclodextrin derivatives indicated the crystalline, anhydrous state of the drug and the amorphous, hydrate nature of the carrier (Fig. 5). Noticeable exothermal effects associated with weight loss were displayed by the derivatives at the lowest substitution degree (MS) in the 215-240°C temperature range. In the case of HP/3Cd MS 0.6 the exotherm peaked at 231°C, with an enthalpy change of 13.5 J g - i (Fig. 5). Comparing the X-ray diffraction and DSC data in Fig. 6 with those for N A P alone (Fig. 5), it is evident that the crystallinity of N A P decreased in equimolar physical mixtures with the a m o r p h o u s 13-cyclodextrin derivatives, and disappeared in the case of NAPHP/3Cd MS 0.9 system when the mixture was kept in an oven for 15 min at 150 + 3°C, a few degrees below the melting point of NAP. DSC analysis allowed us to evaluate the decrease in crystallinity of N A P (AfH= 135 J g - t , mp 156.2°C (Bettinetti et al., 1991b)) through the determination of its specific fusion enthalpy in physical mixtures with /3-cyclodextrin derivatives (values on DSC curves in Fig. 6). The results showed that about 24%, 50% and 80% (as mass fraction) of N A P were brought to an a m o r p h o u s state in equimolar physical mixtures with HE/3Cd MS 0.6, 1.0 and 1.6, respectively. HP/3Cd MS 0.6 was twice as active as HE/3Cd at the same MS (50% compared to 24% N A P amorphized under the same experimental conditions), whilst HP/3Cd MS 0.9 showed the most powerful amorphizing capacity toward NAP. The specific surface area of the carrier (Table 3) seems not to play a role in the solid state interaction between N A P and HE/3Cd, since the derivatives which display the highest and the lowest amorphizing capacity (i.e. HE/3Cd MS 0.6 and 1.6) have the same S w. A contribution of this parameter to the analogous interaction with HP/3Cd can not be ruled out because the m o r e active derivative (MS 0.9) has a surface area
P Mura et al. / European Journal o f Pharmaceutical Sciences 3 (1995) 347-355
354
r.t,
r . t .
156"c
I
5.1
I
/
I
l
15.0
I
25.0 29 jg-I
150"C
20
5.0
I
'
'
I
15.0
I
25.0
~0
c
143"C 50 i00 Temperature,
150 "C
50 i00 150 Temperature, "C
Fig. 6. X-ray powder diffraction patterns (samples at room temperature (r.t.) and kept at 150°C for 15 rain in an oven (150°C)) and DSC curves (10 K min -l) of equimolecular physical mixtures of naproxen (NAP) with hydroxyethyl fl-cyclodextrin (HE/3Cd) with average substitution degree (MS) 0.6 (a), 1.0 (b), 1.6 (c), and with hydroxypropyl fl-cyclodextrin (HPflCd) MS 0.6 (d) and 0.9 (e).
which is twice that of the less reactive one (MS 0.6).
4. Conclusions T h e HE/3Cds and HP/3Cds tested exhibit a similar solubilizing effect (on average 185 times the a q u e o u s solubility, in 0.1 M solution of /3-
cyclodextrin derivative at 25°C) and complexing ability (stability constants about 2300 L mo1-1 at 25°C, docking energy about - 1 5 0 kJ mol -t at 27°C, as from Tables 1 and 2) toward NAP. This is reflected by the i m p r o v e m e n t in the dissolution properties of N A P physically mixed with these a m o r p h o u s carriers, which is m u c h m o r e pron o u n c e d than that o b t a i n e d using the a m o r p h o u s colyophilized p r o d u c t of N A P with native /3-
P. Mura et al. / European Journal o f Pharmaceutical Sciences 3 (1995) 347-355
cyclodextrin. In fact, on the basis of X-ray diffraction and DSC data, a carrier-induced amorphization process of NAP occurs in physical mixtures with both HE/3Cds and HP,BCds. It can be ascribed to a loosening of crystal forces of the drug dispersed within the amorphous carrier phase and seems to be related to the nature of the substituent (HP/3Cd > HE/3Cd) and to MS of the carrier (HE/3Cd MS 1.6 > HE/3Cd MS 1.0 > HE/3Cd MS 0.6; HP]3Cd MS 0.9 > HP/3Cd MS 0.6). Using the molecular modelling procedure it is possible to predict conformation and interaction energy of/3Cd complexes of which crystal structure can not be determined. Docking energy values (Table 2), calculated for some patterns of substituent distribution on a 13Cd molecule, obviously do not reflect the actual situation of random substitution. Nevertheless, these data indicate a more stable inclusion complexation of N A P with chemically modified ]3-cyclodextrins than with native ]3Cd, in agreement with the thermodynamic parameters obtained from solubility studies.
Acknowledgements Financial support from the MURST (60%) and CNR is gratefully acknowledged.
355
References Bettinetti, G.P., Mura, P., Liguori, A. and Bramanti, G. (1989) Solubilization and interaction of naproxen with cyclodextrins in aqueous solution and in the solid state. Farmaco 2, 195-213. Bettinetti, G.P., Mura, P., Melani, F., Giordano, F. and Setti, M. (1990) (S)-(+)-6-methoxy-a-methyl-2-naphthaleneacetic acid and/3-cyclodextrin derivatives: inclusion in aqueous media and solid phase interaction. Minutes, 5th Int. Symp. Cyclodextrins, edited by D. Duchgene. Ed. de Sant~, Paris, pp. 239-242. Bettinetti, G.P., Melani, F., Mura, P., Monnanni, R. and Giordano, F. (1991a) Carbon-13 NMR study of naproxen interaction with cyclodextrins in solution. J. Pharm. Sci. 80, 1162-1170. Bettinetti, G.P., Mura, P., Giordano, F. and Setti, M. (1991b) Thermal behaviour and physicochemical properties of naproxen in mixtures with polyvinylpirrolydone. Thermochim. Acta 199, 165-171. Bettinetti, G.P., Gazzaniga, A., Mura, P., Giordano, F. and Setti, M. (1992) Thermal behaviour and dissolution properties of naproxen in combinations with chemically modified /3-cyclodextrins. Drug Dev. Ind. Pharm. 18, 39-53. Brunauer, S., Emmett, T.H. and Teller, E. (1938) Adsorption of gases in multimolecular layers. J. Am. Chem. Soc. 60, 309-319. Irie, T., Fukunaga, K., Yoshida, A. Uekama, K., Fales, H.M. and Pitha, J. (1988) Amorphous water-soluble cyclodextrin derivatives: 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisobutyl, and carboxamidomethyl derivatives of 13-cyclodextrin. Pharm. Res. 5, 713-717.