Biofarmacia y Farmacociética 447 RELEASE OF SALBUTAMOL ENANTIOMERS FROM HPMC MATRICES ELABORATED BY WET GRANULATION MªAngeles. Solinís1, Yaimy De la Cruz1,2, Alicia R. Gascón1, Rosa Mª Hernández1, Begoña Calvo1, 1Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country, Vitoria -Gasteiz. Spain. 2 Pharmaceutical Chemistry Center. Calle 200 y 21. Atabey. Playa. 11600 La Habana. Cuba. Introduction
Table 1 shows the composition of the matrices
In the last decade, attention has been paid to the elaborated. All materials, with the exception of release of enantiomers of different drugs from lubricants (talc and magnesium stearate), were
formulations containing the racemate. These thoroughly mixed in a mortar and then wetted studies are based on the hypothesis put forward with 20% polyvinylpyrrolidone in ethanol. The wet by Duddu et al in 1993 (1) which assumes that mass was then passed through a 1mm mesh chiral excipients may interact preferentially with sieve and dried at 37ºC for 1 hour. The dried one enantiomer leading to stereoselective granules were then rescreened and a range
release from a formulation containing a between 0.7 and 1mm was collected, lubricated racemate. In previous studies, we considered the and compressed with a reciprocating tablet press release of salbutamol (2,3) and ketoprofen (3,4) machine (BONALS) equipped with cylindrical enantiomers from matrices elaborated by direct punches of 12 mm in diameter and biconvex compression with hidroxypropylmethyl cellulose profile. (HPMC) K100M, a chiral excipient commonly
used in pharmaceutical technology. In these
Table 1. Formulation composition (mg).
studies we observed a small stereoselective
release for ketoprofen but not for salbutamol
sulphate. However, diffusion tests (5) confirmed
the existence of a chiral interaction between
The objective of this study was to investigate if
the use of wet granulation techniques, will allow a
major interaction drug-excipient and will yield
systems showing stereoselectivity in the release
The dissolution studies were performed in
500 mL of Milli-Q water at 37°C and 100 rpm,
Materials and Methods
using the rotating basket (USP 25 apparatus I)
Racemic salbutamol sulphate was obtained (six replicates). The concentrations of R- and S-
from Vencaser S.A. (Bilbao, Spain). salbutamol were analyzed with a Capillary Zone Hydroxypropylmethylcellulose (HPMC) K100M Electrophoresis (CZE) technique (6). was a gift from Colorcon (Kent, UK). The purity of In order to characterize the drug release mode all other reagents was analytical grade or
from the matrices, the data were fitted to the
448 VI Congreso SEFIG y 3as Jornadas TF
Mt/M∞ = K⋅ tn where Mt/M∞ is the fraction of drug in the SG2 composition, because this excipient is
released up to time t, K is the kinetic constant a hydrophilic polymer that favours the HPMC and n is the release exponent indicative of the K100M hydration and influences the polymer release mechanism. The mean dissolution time swelling, the gel barrier formation and,
(MDT) was also calculated. MDT is the mean subsequently, the dissolution of the drug in the ratio of the first to zero moments of the hydrated matrix, favoring the release by diffusion. dissolution rate-time curve. MDT calculations and The presence of mannitol in composition of the the fitting to the equation were performed by formulation SG1 and its influence on the matrix using the WINNONLIN program (8). The paired hydration is the cause that this formulation Student’s t-test was used to compare the kinetics presents a lower value of MDT and a bigger
parameters and the release of the two percentage released. enantiomers in every experiment by using the
statistical program SPSS 10.0 (9). The
Table 2:Values of the kinetic parameters (mean ±
significance level was set at p<0.05.
S.D.). * Statistical significant differences (p<0.05) Results and Discussion K (% h-n) n MDT (h)
Figure 1 shows the dissolution profiles of
SG1 R 29.8±4.9
salbutamol for the formulations SG1 and SG2.
S 31.4±3.7
Both formulations provide an extended release of
SG2 R 22.7±2.0 S 23.5±1.5
Figure 2 shows the R/S ratio of salbutamol
enantiomers released vs time. This ratio is
practically close to unity, although both
formulations show significant differences in the
percentage released between enantiomers in
% Released
some times, concretely, formulation SG1 at 7 and
9 hours and formulation SG2 from 6 to 9 hours.
Moreover, the R/S values are over the unity,
which means that HPMC interacts preferably with
S-salbutamol. This result is in agreement with the
Figure 1:Plots of cumulative percentage of dissolved obtained in the diffusion studies of salbutamol RS-salbutamol vs time for formulations SG1 and SG2.
The results show that both formulations confirm
The values of the kinetic parameters of the stereoselective interaction observed between
salbutamol enantiomers and MDT are listed in salbutamol and HPMC in the diffusion studies,
table 2. The exponent n is indicative of the however this enantioselectivity was not found
release mechanism. When n takes a value of 0.5, from formulations elaborated by direct
the drug is released following a quasi-Fickian compression (2), therefore, the use of wet
diffusion. Values of n between 0.5 and 1, suggest granulation techniques allows a major interaction
that the drug release is controlled by both drug-excipient and favors the chiral interaction.
diffusion of the drug in the hydrated matrix and the erosion of the matrix itself. Formulation SG2 Both formulations show significant differences
shows a bigger value of n and hence the (p<0.05) between enantiomers in the value of n, erosion mechanism plays a more important role although formulation SG2 also shows differences on the release of salbutamol. The difference in in the value of MDT and its R/S ratio is superior. the release mechanism and in the percentage These results show that formulation SG2 released can be due to the absence of mannitol provides a bigger stereoselectivity, although we
Biofarmacia y Farmacociética 449
mechanism plays a more important role on the 2. Solinís MA, Lugará S, Calvo B, Hernández RM, release of salbutamol from this formulation, and
Gascón AR, Pedraz JL. Release of salbutamol
the stereoselective release depends presumably
only on diffusion process (1). The explanation to
hydroxypropylmethylcellulose matrices. Int J
this fact is that the formulation SG2 contains a
bigger amount of HPMC K100M, the 3. Solínis MA, de la Cruz Y, Calvo B, Hernández RM, stereoselectivity is dependent upon the amount
Gascón AR, Goñi I, Gurruchaga M, Pedraz JL.
of chiral excipient in the formulation (2-5). For this
Release of salbutamol sulfate and ketoprofen
enantiomers from matrices containing HPMC and
enantioselectivity in spite of the fact that the
cellulose derivatives. Chirality, 14, 806 (2002).
erosion mechanism (non stereoselective 4. Solínis MA, de la Cruz Y, Hernández RM, Gascón process) is implicated in the release of
AR, Calvo B, Pedraz JL. Release of ketoprofen enantiomers from HPMC K100M matrices.
Diffusion studies. Int J Pharm, 239, 61 (2002).
5. de la Cruz, Y.; Solinís, M. A.; Hernández, R;
Gascón, A.R.; Calvo, B.; Pedraz, J.L. Proceeding
of IV Congreso hispano-luso de liberación
controlada de medicamentos, 71, Vitoria-Gasteiz
6. Esquisabel A, Hernández RM, Gascón AR, Igartua
R/S ratio
salbutamol enantiomers by high performance
capillary electrophoresis and its application to
dissolution assays. J Pharm Biomed Anal, 16, 357
7. Peppas NA. Analysis of fickian and nonfickian
drug release from polymers. Pharm Acta Helv, 60, 110 (1985).
8. WinNonlin. Scientific Consulting Inc North
9. SPSS 10.0. SPSS Inc. Chicago, IL. USA (1999).
R/S ratio 0.85 Acknowledgements
We would like to thank the Basque Government
for the research grants to M.A. Solinís and Y. de
Contact author: Figure 2: R/S ratio of salbutamol enantiomers released vs time. * Statistical significant differences Paseo de la Universidad, nº7 Vitoria-Gasteiz 01006 References
1. Duddu SP, Vakilynejad M, Jamali F, Grant DJW.
Stereoselective dissolution of propranolol
hydrochloride from hydroxypropylmethylcellulose

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