INTRODUCTION:

Simvastatin (SV) is a hypolipidemic drug belonging to the class of pharmaceuticals called "statins". It is a HMG CoA reductase inhibitor. It is used to control hypercholesterolemia (elevated cholesterol levels) and to prevent cardiovascular disease¹. Simvastatin is practically insoluble in water. Poor aqueous solubility may sometimes cause problems of bioavailability like subtherapeutic plasma concentration².

Cyclodextrins comprise a family of non-reducing, water-soluble, cyclic oligosaccharides that are unique in having the ability to form molecular inclusion complexes with hydrophobic drugs having poor aqueous solubility^3,4. These Cyclodextrin molecules are versatile in having a hydrophobic cavity of size suitable enough to accommodate the lipophilic drugs as guests; the outside of the host molecule is relatively hydrophilic.

Thus the molecularly encapsulated drug has greatly improved aqueous solubility and dissolution rate, so CD’s are widely used in pharmaceutical products to reduce problems regarding poor aqueous solubility and bioavailability^5-7.

Only a limited amount of cyclodextrin can be used in many drug formulations and increased efficiency will mean that less CD can be used to achieve the same or even greater solubilising effect. Also, since CD are still relatively expensive, reduction in amount of CD in drug formulation will result in low production costs. It is frequently observed that the drug solubility is notably increased in aqueous solutions due to formation of water-soluble drug-polymer complexes. It is observed that addition of a very small amount of polymer can increase cyclodextrin complexation of drugs in aqueous solutions^8-11.

In present study effect of ternary complex formation of simvstatin:β-cyclodextrin with PVP and HPMC on dissolution rate and solubilising efficiencies were investigated.

MATERIALS AND METHODS:

Simvastatin is a gift sample from Cipla Pharmaceuticals, Goa. β-CD was gift sample from SA Pharmachem Pvt. Ltd., Mumbai. PVP-K-30 (West coast laboratories), HPMC-3000 (S.D. Fine chemicals Ltd. Mumbai) and Methanol (Renkem, Ranbaxy Chem, S.A.S. Nagar) were procured from commercial sources. All other ingredients used were of analytical grade.

Phase solubility studies

Solubility studies were performed according to the method reported by Higuchi and Connors¹². An excess of drug (50 mg) was added to 25 ml portions of distilled water, each containing variable amount of b-CD such as 3-15 mM. All the above solutions with variable amount of b-CD were shaken for 72 hours. After shaking, the solutions were filtered and their absorbance was noted at 237.8 nm. Phase solubility studies were conducted with and without the addition of PVP and HPMC. Hydrophilic polymers were added at a concentration of 0.5% w/v to the solution containing β-CD. The solubility experiments were done in triplicate. The solubility of the SV in every b-CD solutions was calculated and phase solubility diagram were drawn between the solubility of SV and different concentrations of b-CD and polymer. The stability constant of SV-b-CD polymer complex was calculated using Higuchi and Connor’s equation.

Preparation of the complexes

Preparation of solid inclusion complexes of β- CD with Simvastatin was done by kneading method. SV with b-CD in different molar ratios (i.e., 1:1M, 1:2M) were taken. First cyclodertrin is added to the mortar, small quantity of 50% ethanol and dichloromethane (2:1) is added with or without addition of polymers like PVP, HPMC(10%) while triturating to get slurry like consistency. Then slowly drug is incorporated into the slurry and trituration is further continued for one hour. Slurry is then air dried at 25°C for 24 hours, pulverized and passed through sieve no. 100 and stored in desiccators over fused calcium chloride.

Estimation of Simvastatin

A UV Spectrophotometric method was developed and used for the measurement of Simvastatin. The absorbance was noted in phosphate buffer pH 6.8 at λmax = 238.7nm. The method obeyed Beer’s law in the concentration range of 2-10 μg/ml.

Dissolution rate study

In-vitro dissolution of SV inclusion complex was studied in USP XXIII dissolution apparatus (Electrolab) employing a paddle stirrer. 900 ml of phosphate buffer of pH = 6.8 was used as dissolution medium. The stirrer was adjusted to rotate at 50 rpm. The temperature of dissolution media was previously warmed to 37 ± 0.5°C and was maintained throughout the experiment. Complex equivalent to 50 mg of SV was used in each test. 5 ml of sample of dissolution medium were withdrawn by means of syringe fitted with pre-filter at known intervals of time and analyzed for drug release by measuring the absorbance at 238.7nm after suitable dilution with phosphate buffer. The volume withdrawn at each time interval was replaced with fresh quantity of dissolution medium. The dissolution experiments were conducted in triplicate.

RESULTS AND DISCUSSION:

The complexation of Simvastatin with β-CD was investigated by phase solubility studies. Phase solubility diagrams (Figure-1) obtained with β-CD and along with water soluble polymers showed linear relationship between the amount of Simvastatin solubilised and concentration of cyclodextrin in solution. The phase solubility diagram of SV-β-CD complexes can be classified as type A_L according to Higuchi and Connors. Because the straight line had a slope < 1 in each case, the increase in solubility may be attributed due to the formation of 1:1 SV-β-CD inclusion complexes.

Figure 1. Phase solubility diagram of simvastain-β-cyclodextrin complexation in the presence and absence of water soluble polymers.

The values of K_c of various complexes are given in Table-1. The values of K_c indicated that the complexes formed between SV and b-CD are quiet stable. The higher stability constant values in presence of water soluble polymers indicate higher complexation efficiency.

Table-1. Effect of PVP and HPMC on the apparent stability constant (K_c) and solubilising efficiency of Simvastatin and β-CD complexes*

Sample

K_C(M^-1)

Solubilizing Efficiency†

SV-β-CD

SV-β-CD-PVP

SV-β-CD-HPMC

825.5

785.7

766.8

12.28

11.63

11.68

*PVP indicates polyvinyl pyrrolidone; HPMC, hydroxypropyl methylcellulose; β-CD, beta cyclodextrin and SV, Simvastatin.

†Ratio of drug solubility in aqueous solution (15mM) of cyclodextrin (with or without hydrophilic polymers) to drug solubility in water.

The solubilising efficiency of β-CD was calculated to evaluate the effect of hydrophilic polymers which is ratio of the drug solubility in aqueous solution (15mM) of β-CD (with and without hydrophilic polymers) to the drug solubility in water. The solubilising efficiency values are given in Table-1. β-CD alone indicated 12.28 fold increase in solubility of Simvastatin, whereas in presence of water soluble polymers the value was found to be 11.63 and 11.68 respectively for PVP and HPMC.

The dissolution rate of Simvastatin alone and from various solid inclusion complexes was studied under phosphate buffer (pH-6.8). The dissolution of Simvastatin was rapid and higher from all the solid inclusion complexes when compared with simvastatin pure drug. The dissolution profiles of drug and prepared complexes are given in Figure-2. The dissolution of Simvastatin was rapid and higher from all the solid inclusion complexes when compared with pure drug Simvastatin. Dissolution rate constant (K₁) were calculated from first order linear plots of dissolution data. Dissolution efficiency (DE₃₀) values based on dissolution data were calculated as per Khan¹³. T_50%(time taken for 50% dissolution) values were recorded from dissolution profiles. The dissolution parameters are given in Table-2.

Figure-2. Dissolution profiles of Simvastatin and its β-cyclodextrin complxes with or without water soluble polymers.

All the solid inclusion complexes exhibited higher rates of dissolution and dissolution efficiency values than pure drug, which indicates there is rapid and higher dissolution of Simvastatin from β-CD complexes. The values of K₁ and DE₃₀(%) were increased as the proportion of β-CD is increased. The results are shown in Table-2. Higher dissolution rates were observed with the ternary complexes which are prepared by addition of water soluble polymers in comparison with the binary systems which are prepared without addition of polymers also there is marked enhancement in complexation and solubilising efficiency values.

DSC was used to characterize the Simvastatin-β-CD solid complexes prepared with and without polymers. The DSC thermograms of various products are shown in figure-3. The DSC thermogram of SV exhibit an endothermic peak at 138.32 C corresponding to its melting point, the endothermic peak of β-CD showed a broad peak at 91.82 C which may be attributed to a dehydration process. PVP and HPMC showed broad endothermic peaks associated with loss of water. In the thermogram of SV-β-CD, the intensity of endothermic peak was reduced which indicates the weak interaction between SV and β-CD and the DSC thermograms of SV-β-CD-PVP showed slight shift of peak to 133.80 C also the intensity of the peak is markedly reduced. Slight shifting of peaks along with the reduction in the intensity of the peak was observed in case of SV-β-CD-HPMC which suggests the weak interaction and confirms the complex formation.

Figure-3 Differential scanning calorimetry thermograms of Simvastatin and its cyclodextrin complex systems with and without hydrophilic polymers.

Fourier transforms infrared spectra (FTIR) of pure drug (simvastatin), β-CD and various inclusion complexes of β-CD with or without addition of hydrophilic polymers are shown in figure-4. The spectra of pure drug showed very strong peak at 3549cm^-1corresponding to hydroxyl moiety attached to cyclic lactone. The broad C=O peak corresponding to C=O of lactones is noticed at 1722 and1699cm^-1.The C-H ring system exhibited peaks at the 3009, 2955, 2928 and 1699cm^-1. IR spectra of β-CD shows strong broad absorption peak due to OH group is noticed at 3376cm-¹.

Table-2. Dissolution parameters of various Simvastatin- β-CD solid inclusion complexes*

Product	Percent dissolved in 10 min	T₅₀(min)	DE₃₀(%)	K₁(min^-1)	Increase in K₁ (folds)
Pure drug	12.04±0.28	-	15.08	0.0035	-
SV:β-CD(1:1)	29.11±0.67	70	29.25	0.0107	3.08
SV:β-CD(1:2)	31.10±0.30	47	24.07	0.0156	4.47
SV:β-CD:PVP(1:1:0.2)	38.52±0.35	26	39.67	0.0177	5.02
SV:β-CD:PVP(1:1:0.3)	41.18±0.38	15	42.88	0.0275	7.85
SV:β-CD:HPMC(1:1:0.2)	37.91±0.42	24	40.39	0.0194	5.55
SV:β-CD:HPMC(1:1:0.3)	41.55±0.27	15	41.97	0.0263	7.51

*Average of three determination, †Ratio of K₁ of Simvastatin.

PVP molecule along with the expected C-H peaks the broad hump is noticed at 3568cm^-1and 3161cm^-1corresponding to polymeric nature of PVP also the cyclic C=O peak exhibit absorption at 1693cm^-1. HPMC give a broad absorption peak from 3500cm^-1to 3215cm-¹which is the characteristic property of polyhydroxyl molecule. Inclusion complexes showed the absence of above noted peaks which confirms the complex formation.

Figure-4 Fourier transformed infrared spectras of powder samples of Simvastatin and its complexes with β-CD and hydrophilic polymers.

Much higher rates of dissolution were observed with the ternary system of drug: β-CD: polymer which may be due to better complexation.

CONCLUSION:

Phase solubility diagram confirmed the formation of 1:1 molar complex of drug: β-CD with or without addition of hydrophilic polymers. Complex formation was also confirmed by FT-IR and DSC studies. Much higher dissolution rates were observed with inclusion complexes of β-CD along with hydrophilic polymers in comparison to pure drug and its complexes with β-CD alone. The order of hydrophilic polymers enhancing dissolution rate of β-CD complexes was PVP > HPMC. Marked improvement in the dissolution efficiency values were observed with the addition of hydrophilic polymers.

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Received on 19.04.2010 Modified on 04.05.2010

Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page 1148-1151