(T1030-01-04) Solubility Enhancement of Atorvastatin Calcium Using Cyclodextrin

Purpose: One of the most known challenges during drug development and delivery is associated with poorly soluble drugs resulting in low bioavailability. The commonly used methods to enhance solubility, such as physical modification of the entities, tend to increase solubility to a limited extent. However, when it comes to high-dose formulations with low hydrophilicity and high melting points, these conventional methods don’t fulfill the objectives. Different techniques to improve the solubility are adding surfactants, polymorphism, salt formation, micronization, etc. But they also have their own limitations. Atorvastatin calcium, as a synthetic lipid-lowering agent, is an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme. An (HMG-CoA) reductase which catalyzes the conversion of HMG-CoA to mevalonate, is an early rate-limiting step in cholesterol biosynthesis, and it is currently used as calcium salt for the treatment of hypercholesterolemia (1). It is absorbed quickly after oral administration but leads to first-pass metabolism in the liver and gut wall which justifies its low oral bioavailability. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic bioavailability of HMG CoA reductase inhibitory activity is approximately 30% (2). Cyclodextrins (CDs) have been used to complex drugs having low hydrophilicity by forming inclusion complexes. When drug molecules interact with CDs they result in the formation of inclusion complexes, with the lipophilic cavity of the CDs (host molecule) providing a benefit for the entrapment of drugs that aren't very soluble in water. Aqueous solutions containing CDs cause polar water molecules to enter the chamber of the CDs (3). Solvent Assisted Extrusion (SAE) is a continuous process and allows uniform mixing and an enhanced intermolecular interface compared to conventional complexing methods. The primary goal of this study was to combine cyclodextrin with atorvastatin calcium to increase its solubility and rate of dissolution.

Methods: An 11mm twin-screw extruder (Thermo Fisher Scientific, MA, USA) was used for solvent-assisted extrusion. As shown in composition table, different formulations were prepared using different techniques and compared for solubility and dissolution rate. Phase solubility studies between the drug and cyclodextrins (A-CD, B-CD, G-CD, HPBCD, HPGCD) were performed to check the compatibility. The formulations were prepared by the physical mixture, kneading method, and solvent-assisted extrusion method at 1:1 (Drug: CD) molar concentrations. Saturation solubility tests were performed for the drug and final formulation (SAE). Differential Scanning Calorimetry (DSC), and Fourier Transforms Infrared (FTIR) tests were evaluated to check the inclusion complexation. The in vitro release study was carried out using a USP dissolution apparatus II in 900 mL pH 6.8 phosphate buffer, with the temperature maintained at 37.5℃ and a paddle rotation speed set at 75 rpm.

Results: The saturation solubility was conducted in water for pure API ATN and was evaluated using the HPLC. The solubility of pure API (Atorvastatin Calcium) ATN was found to be 0.0167mg/ml in water. The dried product obtained from kneading method was subjected to a solubility study. The solubility of this complex was found to be 0.251mg/ml. By using solvent-assisted extrusion (SAE) complexes that were formed through this technique were evaluated for their solubility in water found to be 0.294mg/ml resulted in a slight increase in solubility over the physical mixture and kneading mixture. By DSC studies it was found that Complexation of the drug and cyclodextrin results in the shifting of the peak to less temperature or complete loss of the peak depicting the change from crystalline to amorphous nature. FTIR is used evaluates the drug cyclodextrin interactions to confirm the formation of an inclusion complex. The dissolution study has revealed the formation of an inclusion complex between ATN Ca and HPBCD using SAE, resulting in superior dissolution rates.

Conclusion: ATN Ca-HPBCD complex, one of the complexes created using the SAE procedure, showed a significantly increased solubility compared to the plain drug. Due to its superior solubility, the inclusion complex prepared by the SAE technique also demonstrated faster drug release compared to the complex prepared by the kneading technique and the pure drug alone. Altogether an increase in solubility of ATN Ca was seen with the SAE technique, which supports the objective of this study that SAE is a successful method for formulating drug-cyclodextrin complexes.

References: 1. Daily Med - ATORVASTATIN CALCIUM- atorvastatin calcium tablets tablet [Internet]. [cited 2023 Apr4]. Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=803b7d6f-faea-4a13-a141-f2c44d7fca72
2. Palem CR, Patel S, Pokharkar VB. Solubility, and stability enhancement of atorvastatin by cyclodextrin complexation. PDA J Pharm Sci Technol. 2009;63(3):217–25.
3. Challa R, Ahuja A, Ali J, Khar RK. Cyclodextrins in drug delivery: An updated review. AAPS PharmSciTech. 2005 Jun;6(2): E329–57.

Formulation and Composition of HME extrudates

solubility and dissolution studies

DSC and FTIR studies of HME extrudates