1. Improving the Stability of Atorvastatin: Kinetic Studies
of the Degradation in Acidic Solutions Usama Farghaly Aly Faculty of Pharmacy, El-Minia University
Introduction
Objective
Results
Results
Atorvastatin (ATV) is a lipid-lowering agent act by inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme. It also slow the progression of atherosclerosis by inhibiting monocyte activation, metalloprotease synthesis in the vessel wall and the production of proinflammatory cytokines such as interleukin (IL)-6, tumour necrosis factor (TNF)-a and IL-1b (Lennernas, 2003, Ferro, 2000 and Solheim, 2001 )
Figure 1: Structure of Atorvastatin
Unfortunately, atorvastatin is an unstable substance sensitive to heat, humidity, low pH of the environment, and light, particularly UV radiation. Carbon dioxide is thought to be the most important factor leading to the instability of the drug. Its effect is ascribed to the lowering of pH, which results in the decomposition of hydroxyacids particularly to their lactones (Pavel, 2007)
Numerous methods have been devised in pharmaceutical field to improve the stability of drugs. These methods may include complexations with -cyclodextrins. Nevertheless, the usefulness of natural cyclodextrins has been limited by relatively low aqueous solubility particularly, - cyclodextrin, Hydroxypropyl--cyclodextrins (HP--CDs) have the advantage of greater aqueous solubility and safety compared with -cyclodextrin. The greater solubility and safety of HP--CDs are probably attributed to their amorphous, noncrystalline structures (Stella, 1997)
The second method is the addition of a basic polymer, like PVP. Regarding ATV, this may contribute in stabilizing the drug through increasing the pH of the dosage form in which ATV is contained (Pavel, 2007)
Another important approach is the use of antioxidants. In this study quercetine, a natural flvonoid, was selected for the purpose of stabilization because of its antioxidant effect , in addition, it may synergize the action of ATV as it has a lipid-lowering effects (Formica, 1995)
Finally, both the stability and the dissolution of ATV can be improved, simply, by elevating the pH, but, it is pointed out that gastric troubles may be caused if a medicine with a high content of alkaline substance is administered to patients
In this study, different methods were investigated in order to improve the stability of the drug including complexation with hydroxypropyl--cyclodextrin, preparation of solid dispersions with PVP k-30, and a ternary system of both, the use of an antioxidant and elevatating the pH by the addition of a basic substance, like disodium hydrogen phosphate(DSHP)
It is important to say that all the methods employed in this study will improve the dissolution of the drug (Usama, 2011)
Results showed a marked instability of Atorvastatin in acidic solutions at 70 C (about 71 % degraded within 120 hours).
All the prepared systems showed an improvement in the drug stability. The addition of quercetine, a potent antioxidant, to ATV resulted in a slight improvement in the stability (k= 7.36 x10-3 hr-1), while, maximum stability was produced by the ternary system, as 39 % only were degraded within the same period, k= 4.14 x However, the addition of quercetine to the ternary system did not produce a marked improvement in the stability of the drug (k= 3.91 x 10-3). Other systems produced moderate effects on the stability of ATV
Similar observations were noticed upon studying the stability at 30 C
The main objective of this work was to evaluate the potential of different methods in improving the stability of ATV. And hence, obtaining a drug with more acceptable physical qualities
Methodology
To improve the stability of the drug, numerous systems of Atorvastatin were prepared and investigated kinetically, at 30 C and 70 C, for the degradation of the drug in 0.1 N HCl. The prepared systems are shown in table 1:
Preparation of Solid Complexes.
The preparation of solid complexes of ATV and HP--CD were performed by the evaporation method. The molar ratio was kept at 1:1, based on the results of the phase solubility diagram (Figure 1). After dissolving HP--CD in methanol, the 1:1 molar proportion of ATV was added. This solution was kept under stirring for 12 hours in glass stoppered bottles. Then, it was allowed to evaporate at a temperature of 45°C and 100 rpm in a rotary evaporator. The solid residue was further dried at 45°C for 12 hours, pulverized and sieved to obtain a particle size range of µm using USP sieve set and kept in a desiccator over anhydrous calcium chloride until used .
Preparation of Solid Dispersions with a Basic Polymer (Polyvinylpyrrolidone)
The solvent evaporation of ATV and PVP K-30 solution in ratios (1:1 w/w) was carried out by using Rota evaporator (Heidolph, Germany). Both the drug and the polymer were weighed accurately and dissolved separately in methanol to obtain a clear transparent solution. The two solutions were mixed and vortexed for 30 min. Subsequently, the solution was transferred to rotary evaporator at a temperature of 45°C and 100 rpm. The solid residue was further dried at 45°C for 12 hours, as mentioned
Preparation of a ternary system (ATV/PVP/HP--CD).
The ternary systems containing ATV:HP--CD:PVP in a ratio 1:1:1 were prepared using co-evaporation method (in methanol) . All ATV, HP--CD, and PVP are mixed together then co-evaporated. Co-evaporation processes were carried out using Rota evaporator by the same method mentioned above
Figure 2: Phase solubility diagram
Table (1) Composition of the prepared systems.
System
Composition I
ATV:PVP k-30 (1:1) solid dispersions. II
ATV:HP--CD (1:1) inclusion complex.
III
ATV:HP--CD:PVP (1:1:1) ternary system. IV
ATV plus disodium hydrogen phosphate (1:1) V
ATV:Quercetine (QRT) (1:1) solid dispersions VI
Ternary system to which QRT was added.
Conclusion
The stability of atorvastatin could be improved by numerous methods
These methods include; complexation with HP--CD, solid dispersions with a basic polymer as PVP k-30, or using a ternary system of both
In addition, natural antioxidants, like quercetine, may also protect the drug against decomposition
References
Figure 3: The first-order degradation of ATV and other prepared systems in 0.1 N HCl at 70 C.
Ferro D, Parrotto S, Basili S, Alessandri C, Violi F. Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia. J Am Coll Cardiol 36: 427–431,(2000).
Formica J., and Regelson W., Review of the biology of quercetin and related bioflavonoids, Food ChemToxicol, 33: , (1995).
Lennernas, H. Clinical pharmacokinetics of atorvastatin. Clin. Pharmacokinet., 42, 1141–1160, (2003).
Pavel S, Alena P, Eduard S, Stanislav R, Jan S, Martin S, Andrej K, Adrian D, Roman P, Miroslav S. Methods for the stabilization of Atorvastatin. European patent EP B1,(2007).
Solheim S, Seljeflot I, Arnesen H, Eritsland J, Eikvar L. Reduced levels of TNF alpha in hypercholesterolemic individuals after treatment with pravastatin for 8 weeks. Atherosclerosis 157: 411–415, (2001).
Stella VJ, Rajewski AR., Cyclodextrins: Their future in drug formulation and delivery. Pharm Res 14:556–567, (1997).
Usama FA., Enhancement of solubility and dissolution of atorvastatin: In vitro and in vivo evaluation, Alex J Pharm SCI, 25(2): 83-90, (2011).
Figure 4: The first-order degradation of ATV and other prepared systems in 0.1 N HCl at 30 C
Table 2: The observed first-order rate constant (K) for ATV and other prepared systems in 0.1 N HCl at 70 C and 30 C.
Acknowledgement
I would like to express my deep gratitude to Prof. Dr. Khaled Aly Khaled, Professor of Pharmaceutics, Faculty of Pharmacy, Al-Minia University, Al-Minia, Egypt, for constant advise, moral support and helpful criticisms