ELSEVIER European Journal of Pharmaceutical Sciences 3 (1995) 347-355

E U R O P E A N J O U R N A L 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.

Keywords: Naproxen; Hydroxyethyl /3-cyclodextrin; Hydroxyproyl /3-cyclodextrin; Phase-solubility analysis; Molecular modelling; X-ray diffractometry; Differential scanning calorimetry; Thermogravimetric analysis

1. Introduction

Naproxen ((S)-(+)-6-methoxy-a-methyl-2-na- phthaleneacetic 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 hydroxy- propyl fl-cyclodextrin (HPflCd) with MS 0.6 and

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0.9 was investigated. Phase-solubility analysis at different temperatures and the molecular model- ling approach were the methods used to investi- gate the interaction of NAP with these /3Cd derivatives and to complement previous C-13 NMR results on NAP-HP/3CD MS 0.9 and NAP- HE/3CD MS 1.6 systems (Bettinetti et al., 1991). In the study of NAP-cyclodextrin inclusion com- plexation, phase-solubility analysis was com- plemented by computer-aided molecular model- ling. The effect of the solubility enhancement on drug dissolution rate was determined by testing physical mixtures of NAP and each /3-cyclodex- trin derivative in the 1:1 (mol/mol) ratio accord- ing 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 demon- strate possible drug-carrier interactions in the solid state.

concentration was determined by a second de- rivative ultraviolet absorption method at 274 nm (Bettinetti et al., 1989). Each experiment was performed in triplicate.

2. Experimental procedures

Materials. Naproxen (NAP) (Sigma Chemical Co, St. Louis, MO, USA), hydroxyethyl /3- cyclodextrin (HE/3Cd) with an average substitu- tion degree per anhydroglucose unit (MS) of 0.6, 1.0 and 1.6 (donated by Wacker-Chemie GmbH, Munich, Germany) and hydroxypropyl /3- cyclodextrin (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 (deter- mined 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 deter- minations were performed with a surface area analyser Flowsorb II 2003 (Micromeritics, Geor- gia, 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 deter- mined 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 (75- 150/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 /3- cyclodextrin derivative in the 5-100 mmol L -I concentration range, in a sealed glass container which was electromagnetically stirred at a con- stant temperature (25, 37 or 45°C) until equilib- rium was achieved. An aliquot was withdrawn and filtered (pore size 0.45 mm), and the NAP

Dissolution studies. Dissolution rates of NAP from physical mixtures of the drug (75-150 /xm sieve granulometric fraction) with each /3- cyclodextrin 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-cyclodex- trin (/3Cd), were determined in water at 37-+ 0.3°C according to the dispersed amount and rotating disc methods. Dispersed amount experi- ments were performed under non-sink condi- tions, by adding 100 mg of NAP or NAP equiva- lent 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 main- tained 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) 347-355 349

nologies, San Diego, CA, USA). The /3- cyclodextrin 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 ex- amined for the tetra-substituted fl-cyclodextrins, and three for the hexa-, epta- and the undeca- substi tuted ones, respectively. NAP was fitted into the cavity in an axial orientation, with the carboxyl group directed toward the widest rim of the cavity (Bettinett i et al., 1991). Each structure was subjected to a process of energy minimiza- tion (CVFF force field, D I S C O V E R 2.9 pro- gram, Biosym Technologies), performing itera- tions to a <0.05 derivative value. Molecular dynamic simulations were performed at 27°C (t ime step 1 fs, equilibrium time 100 fs, step number 10000). Docking energies were calcu- lated at both -273°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. Tempera ture and enthalpy measurements 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. Thermogravimetr ic analysis (TGA) was conducted on a Mettler TG 50 apparatus (5 or 10 K min -~) on 15-25 mg samples in alumina crucibles under a nitrogen atmosphere (10 mL/ rain).

X-ray analysis. X-ray diffraction patterns were collected with a computer-control led Philips PW 1800 apparatus in the 2-40 ° 20 interval (scan rate 1 ° m in - l ) , using a CuKa radiation mono- chromatized with a graphite crystal. Spectra of NAP-cyclodextrin blends were recorded at room tempera ture 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 promoted by HPflCd MS 0.9 and

HE/3Cd MS 1.6 is dependent on the formation of an inclusion complex with the respective /3Cd derivative (Bettinetti et al., 1991). In the pres- ence of HP/3Cd MS 0.6 and HE/3Cd MS 0.6 and 1.0, the NAP solubility linearly increased follow- ing the A L type phase-solubility diagram (Fig. la). The relative increase in the presence of 100 mmol L -~ of each /3Cd derivative at 25°C, 37°C, and 45°C was more pronounced at the lowest temperature (Fig. lb). The increase resulted 200- times the NAP solubility for the HP/3CD MS 0.9 derivative and somewhat less for the other cyclodextrins.

The thermodynamic parameters obtained from the temperature dependency of the apparent 1:1 stability constants of the inclusion complexes within the 25-45°C tempera ture range are shown in Table 1, with those of the NAP-/3Cd inclusion complex (Bettinetti et al., 1989) for coNparison.

2O

o 15 E E

10 D . , <

Z 5

U

• | - i - i ! • 1

0 2 0 4 0 6 0 8 0 1 0 0 c(Cd), mmot/L

(b) 2soc 200"1 HESCd [ HPI3Cd ~ ;~

3 7 = C

~ 4Soc

MS 0.6 1 1.6 0.6 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 AG~5o c AH ° /xS°5.c K~1:~ ) (L mol -z) (kJ mol -~) (kJ mol -~) (J mol -~ K-~)

25°C 32°C 37°C 45°C

~Cd 1702 1482 1388 - -18.5 -13 .2 17.6

HE~Cd 0.6 2337 - 1716 1539 -19.2 -16 .8 8.1 HE~Cd 1.0 2175 - 1745 1358 -19.0 -18.2 2.8 HE~Cd 1.6 2145 - 1800 1729 -19.0 -8 .7 34.5 HP~Cd 0.6 2083 - 1726 1694 -18.9 -12 .0 23.1 HP~Cd 0.9 2580 - 1976 1464 -19.4 -17.1 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 mecha- nism.

3.2. Molecular modelling

Computer-generated structures of NAP- HE/SCd inclusion complexes are shown in Fig. 2. Van der Waals energy values of docking between some/3-cyclodextrins (host) and NAP (substrate) at -273 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 glu- coses 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 -273 and 27°C (standard deviation for values at 27°C in parentheses)

Cyclodextrin Substituent Distribution per/SCd of substituents mole

Docking energy (kJmol - t )

-273°C 27°C

/SCd - - -149 -140 (8) HE/SCd 0.6 4 (a) - 173 - 153 (8) HEflCd 0.6 4 (b) -177 -145 (7) HE/SCd 0.6 4 (c) - 174 - 152 (7) HE/SCd 1.0 7 (a) - 181 - 157 (9) HE/3 Cd 1.6 11 (d) - 185 - 162 (9) HP/SCd 0.6 4 (a) - 182 - 150 (8) HP/SCd 0.6 4 (b) - 164 - 143 (9) HP/SCd 0.6 4 (c) - 159 - 152 (6) HP/3Cd 0.9 6 (a) - 192 - 154 (8)

(a) Substituents at the level of primary OH groups distributed equally between the glucoses. (b) Three substituents clustered on one glucose, the fourth on a primary OH group. (c) Substituents forming on oligomeric chain on a primary OH group. (d) Seven substituents on primary OH 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.

HE/3Cd MS 1.6 when the relative position of glucoses substi tuted at the level of secondary O H groups within pat tern (d) was varied (e.g., 1-2-5-6 or 1-3-5-7). As can be seen in Table 3, statistical- ly significant differences (P < 0.05) were instead found be tween the docking energy values of the interactions of N A P with /3Cd and its hydroxy- alkyl derivatives, except be tween patterns (a) and (c) of HE/3Cd MS 0.6.

3.3. Dissolution tests

The noticeable improvement in the propert ies of N A P dissolution from its equimolar physical mixtures with all the /3-cyclodextrin derivatives tested (Fig. 3a) can be at t r ibuted to the inclusion complex format ion as well as to an increase in drug wettability and a decrease in N A P crys- tallinity (see below). It should be highlighted that

352 P. Mura et al. / European Journal o f Pharmaceutical Sciences 3 (1995) 347-355

(a) (b)

2 5 0 ~ 20

200

15o o. ,¢ z 100

50

10

Cc C C 0 0

• ! • i • i • i • i • i

0 10 20 30 40 50 60 time (rain)

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 HEflCd HPflCd

MS - 0.6 1.0 1.6 0.6 0.9 S, (m2/g) 0.64 0.64 0.79 0.64 0.86 1.78

this improvement was also clearly higher than from the NAP/fl-cyclodextrin colyophilized prod- uct, which previously showed the best dissolution properties in comparison with the corresponding physical mixture, coground and coevaporated products (Bettinetti et al., 1989). A comprehen- sive picture of the relative increase in the initial amount of NAP dissolved in the dissolution

30

. J E 20 ::L

a. 10 z

( a ) 150 -

[] k = lo.9 ~ , = d s • k = lo.~ ~ . , ~ ' a k= 9.0 . ~ ' ~ . ~ 0 k= 2.5 ~ / I f ~ 100'

~ - - - ~ - - . , = . ; , ; .

0 100 200 300 time (s)

0 MSO 0.6

( b )

27%

1 1.6

HPGCd

L._ /----

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 CV<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) 347-355 353 medium is given in Fig. 3b. Dissolution tests were also performed on non-disintegrating tablets at constant surface area to avoid effects of particle size and hence specific surface area. The results showed a similar t rend to the dispersed amount experiments (Fig. 4a). The improvement in NAP dissolution rate occurred to about the same extent for the various carriers tested. The NAP dissolution rate constants, calculated from the linear port ion of dissolution profiles of com- pressed physical mixtures with /3-cyclodextrin derivatives, were on average 10 /xg cm -2, two order of magnitude higher than those of NAP alone (0.09/zg cm -2) and for times that of NAP- 13Cd colyophilized product (2.5 /xg cm-2). The

'" - L . . . . 1 ....

50 I00 : 150 200 250 300 *C

t .0_01 ~ ~r~

0.00 I i l

5,0 15.0 25~.0 2 "O

Fig. 5. DSC (5 K min -1) and TGA (5 K rnin -~, dashed line) curves of naproxen (NAP) and hydroxypropy113-cyclodex - trin (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).

relative increase in NAP dissolution rate is shown in Fig. 4b.

3.4. Interaction in solid state

Thermal behaviour and X-ray powder diffrac- tion patterns of NAP and /3-cyclodextrin deriva- tives indicated the crystalline, anhydrous state of the drug and the amorphous , hydrate nature of the carrier (Fig. 5). Noticeable exothermal ef- fects 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 ex- otherm 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 NAP alone (Fig. 5), it is evident that the crys- tallinity of NAP decreased in equimolar physical mixtures with the amorphous 13-cyclodextrin de- rivatives, and disappeared in the case of NAP- HP/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 NAP (AfH= 135 J g- t , mp 156.2°C (Bettinetti et al., 1991b)) through the determinat ion 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 NAP were brought to an amorphous 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% NAP 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 NAP 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 more active derivative (MS 0.9) has a surface area

354 P Mura et al. / European Journal o f Pharmaceutical Sciences 3 (1995) 347-355

r . t ,

I

5.1

156"c

I I l

15.0 25.0 20

r . t .

/ 150"C

I I ' ' I I

5.0 15.0 25.0 ~0

29 jg-I c

143"C

50 i00 150 50 i00 150 Temperature, "C 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

The HE/3Cds and HP/3Cds tested exhibit a similar solubilizing effect (on average 185 t imes the aqueous solubility, in 0.1 M solut ion of /3-

cyclodextr in 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 f rom 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 proper t ies of N A P physically mixed with these amorphous carriers, which is much more pro- nounced than that ob ta ined using the a m o r p h o u s colyophil ized produc t of N A P with native /3-

P. Mura et al. / European Journal o f Pharmaceutical Sciences 3 (1995) 347-355 355

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 struc- ture can not be determined. Docking energy values (Table 2), calculated for some patterns of substituent distribution on a 13Cd molecule, obvi- ously do not reflect the actual situation of ran- dom substitution. Nevertheless, these data indi- cate a more stable inclusion complexation of NAP with chemically modified ]3-cyclodextrins than with native ]3Cd, in agreement with the thermodynamic parameters obtained from solu- bility studies.

Acknowledgements

Financial support from the MURST (60%) and CNR is gratefully acknowledged.

References

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