Enhancement of solubility and dissolution rate of atorvastatin calcium by co-crystallization

Yudi Wicaksono,Tri A Siswoyo,Budipratiwi Wisudyaningsih

doi:10.4314/tjpr.v16i7.6

Yudi Wicaksono, Tri A Siswoyo + Show 1 more

Open Access

https://doi.org/10.4314/tjpr.v16i7.6

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Abstract

Purpose: To investigate the formation of atorvastatin calcium (AC) co-crystal to improve its solubility and dissolution rate.Method: Co-crystallization of AC in equimolar ratio with isonicotinamide (INA) was carried out by slow solvent evaporation method using methanol. The solid obtained was characterized by powder x-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and then further evaluated for solubility and dissolution.Results: The PXRD pattern of ACINA showed new crystalline peaks at 2θ values of 8.2 and 18.3o, indicating the presence of a new crystalline phase of ACINA co-crystal. The DSC thermogram of ACINA displayed a melting point at 201.7 oC which is higher than the melting points of AC (159.4 oC) and INA (158.0 oC). The FTIR spectra of AC in ACINA shifted the absorption peak from 3363 to 3280 cm-1 and to 1216 to 1222 cm-1. The absorption peak shift is presumably due to N-H and C-N groups of AC form the hydrogen bonding interaction with groups in INA molecule. The solubility of ACINA co-crystal in distilled water was 270.7 mg/L which is significantly higher (p < 0.05) than that of pure AC (140.9 mg/L). The dissolution rate of ACINA co-crystal was 2 - 3 times faster than that of pure AC.Conclusion: AC and INA in equimolar ratio forms a co-crystal by slow solvent evaporation. ACINA cocrystal significantly increases in solubility with a dissolution rate 2 - 3 times faster than that of pure AC. The enhancement of aqueous solubility and dissolution rate of AC with co-crystallization may be a potential way to solving the bioavailability problem of AC.Keywords: Atorvastatin calcium, Co-crystal, Isonicotinamide, Solubility, Dissolution rate

Highlights

Atorvastatin calcium (AC), ([(R-(R*,R*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid), which is calcium salt (2:1) trihydrate ([C33H34FN2O5]2Ca.3H2O), is considered one of the most effective synthetic lipid lowering agents 1,2
Co-crystal is defined as a non-single component system consisting of various components that are completely solid under ambient conditions and attached with non-covalent bonds such as hydrogen bonds, aromatic-aromatic interactions and van der Waals bonds 6,9,10
differential scanning calorimetry (DSC) curve of ACINA showed different endothermic peak with atorvastatin calcium (AC) and INA, which was observed at 201.7 C

Summary

Introduction

Atorvastatin calcium (AC), ([(R-(R*,R*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid), which is calcium salt (2:1) trihydrate ([C33H34FN2O5]2Ca.3H2O), is considered one of the most effective synthetic lipid lowering agents 1,2. The drug is administered orally to reduce total cholesterol, low density lipoprotein and triglycerides 3. AC has very good intestinal permeability but it has poor aqueous solubility 4. This is caused oral by the bioavailability of AC of only about 12 - 14 % 1,5. Enhancement of aqueous solubility of AC may be a potential way to solving the bioavailability problem of AC 3. Co-crystallization is one of the techniques generally implemented by researchers to fix the physicochemical properties of an active pharmaceutical ingredient (API) 6-8. Co-crystal is defined as a non-single component system consisting of various components that are completely solid under ambient conditions and attached with non-covalent bonds such as hydrogen bonds, aromatic-aromatic interactions and van der Waals bonds 6,9,10

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