(M1430-03-16) Solubility Enhancement of Atorvastatin Calcium Trihydrate by Melt Extrusion

Purpose: The solubility of the drug is a significant aspect to be considered during the manufacturing of pharmaceutical products. Poor solubility of drugs imparts depleted bioavailability. In this regard, several techniques are available for enhancing drug solubility or dissolution. Hot-melt extrusion (HME) is one such technique that has been widely used in the industry. It is a single-step, continuous manufacturing, and scalable method that has proved successful in improving the solubility of poorly soluble drugs. Atorvastatin calcium trihydrate is the most preferred molecule among statins, used to treat moderate to severe familial or non-familial hypercholesterolemia, and is introduced by Pfizer Inc., USA as Lipitor®. In this study, ATH (Atorvastatin calcium trihydrate) formulations were prepared with HPMC K100 LV and optimized Plasticizer (PEG 3350) via hot-melt extrusion (HME) at different extrusion temperatures to evaluate the effect of plasticizer on the process of HME. The primary goal of this study is to increase the solubility and rate of dissolution.

Methods: A 6 mm (minilab) extruder (Thermo Fisher Scientific, MA, USA) was used for extrusion. The HME filaments were granulated using a motor and pestle and passed through a 30-mesh sieve to obtain the uniform size granules. Differential Scanning Calorimetry (DSC) was performed to evaluate the glass transition temperature (T_g), and melting temperature (T_m) of both the drug and the polymeric carrier. Tablets are compressed by direct compression. Tablet’s hardness and disintegration time were evaluated. As shown in Table 1 different compositions of formulations were prepared and compared for dissolution rate. In vitro release study for the tablets was carried out using a USP dissolution type-II paddle apparatus (Hanson SR8- plus TM) at 75 rpm in pH 6.8 phosphate buffer. Samples were analyzed for Atorvastatin calcium trihydrate using the UV method at 241 nm.

Results: Tablets of all optimized formulations were successfully prepared by the direct compression method and disintegrated within 15 mins. From the in vitro drug dissolution testing, formulation F5 showed the complete drug release in 30 mins because of the highest concentration (50%) of Polyethylene glycol 3350 (Plasticizer) used. The F0 formulation showed the lowest % drug release (44.04%) in 30 mins as no Polyethylene glycol 3350 was used. The F4 and F5 formulations showed similar drug release (F4 40% and F5 50% Polyethylene glycol 3350 used) (Figure 1). Table 2 explains the various dissolution parameters such as Q15 (Percentage drug release in 15 min), IDR (Initial dissolution rate), and DE (Dissolution efficiency), and among all formulations, F5 is superior in these results.

Conclusion: In this study, Polyethylene glycol 3350 was selected as an optimized plasticizer for the preparations for ATH formulations. The F5 contains 50% of plasticizer and shows the highest drug release compared to F0 without plasticizer which shows the least drug release. As an increase in the plasticizer among the formulations the increase in the % drug release is seen, which supports the objective of this study. All the formulations contain 20% drug load. It is worth mentioning that the dissolution profile rate of physical mixtures of all formulations shows less drug release than that of HME formulations.

References: 1. Amit Chivate, Atul Garkal, Namdev Dhas and Tejal Mehta, PDA Journal of Pharmaceutical Science and Technology July 2021, 75 (4)357-373.
2. Khan, F.N., Dehghan, M.H.G. Enhanced Bioavailability of Atorvastatin Calcium from Stabilized Gastric Resident Formulation. AAPS PharmSciTech 12, 1077–1086 (2011).

Composition of Formulations

Dissolution Parameters of formulations

Dissolution Profile of Formulations