Lacidipine Amorphous Solid Dispersion Based on Hot Melt Extrusion: Good Miscibility, Enhanced Dissolution, and Favorable Stability
The present study aimed to increase the in vitro dissolution rate of lacidipine, a poorly water-soluble drug, by formulating amorphous solid dispersions (ASDs) using hot-melt extrusion (HME). Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, and Fourier transform infrared were used to characterize the optimal formulations and evaluate the physical stability for the stress test. Film-casting method and hot-stage microscopy were applied to study the miscibility of lacidipine and the drug carriers. In vitro dissolution tests were conducted as the final evaluation index. The optimal formulations were successfully obtained with Soluplus and PVP VA64 at a drug/carrier ratio of 1:10 (w/w), Fourier transform infrared studies revealed the hydrogen bonding between drug and polymers, and in vitro dissolution rates of the optimal formulations were extremely enhanced compared to bulk lacidipine and physical mixtures, similar with that of the commercial tablet. The ASD formulated with Soluplus showed better physical stability than that with PVP VA64. A strong hydrogen bonding and good drug-polymer miscibility were essential to hinder the recrystallization of lacidipine ASDs. In conclusion, the lacidipine ASD formulated with Soluplus showed a significant increase in in vitro dissolution rate and favorable physical stability in the stress test.
KEY WORDSlacidipine hot-melt extrusion dissolution amorphous solid dispersion physical stability
This work was financially supported by the National Nature Science Foundation of China (No. 81502993), by the Nature Science Foundation of Liaoning Province (No. 201700287), by the Basic Research Projects of Universities of Liaoning Provincial Department of Education (2017LQN02), and by the Career Development Program for Young Teachers in Shenyang Pharmaceutical University.
- 2.Fu Q, Li B, Zhang D, Fang M, Shao J, Guo M, et al. Comparative studies of the in vitro dissolution and in vivo pharmacokinetics for different formulation strategies (solid dispersion, micronization, and nanocrystals) for poorly water-soluble drugs: a case study for lacidipine. Colloids & Surfaces B Biointerfaces. 2015;132:171–6.CrossRefGoogle Scholar
- 7.Donovan MJ, Saleem I, Smyth HDC. Pharmaceutical applications of hot-melt extrusion: part II. Ichnos An International Journal for Plant & Animal Traces. 2008;14(3):215–7.Google Scholar
- 8.Baronsky-Probst J, Möltgen CV, Kessler W, Kessler RW. Process design and control of a twin screw hot melt extrusion for continuous pharmaceutical tamper-resistant tablet production. European Journal of Pharmaceutical Sciences Official Journal of the European Federation for Pharmaceutical Sciences. 2016;87:14–21.CrossRefGoogle Scholar
- 14.Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. European Journal of Pharmaceutics & Biopharmaceutics Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E V. 2000;50(1):47.Google Scholar
- 15.Bruce LD, Shah NH, Malick AW, Infeld MH, Mcginity JW. Properties of hot-melt extruded tablet formulations for the colonic delivery of 5-aminosalicylic acid. European Journal of Pharmaceutics & Biopharmaceutics Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E V. 2005;59(1):85–97.Google Scholar
- 17.Vasconcelos T, Sarmento B, Costa P. Solid dispersion as strategy to improve oral bioavailability of poof water soluble drugs. Drug Discov Today. 2008;12(23–24):1068–75.Google Scholar
- 27.Kassem MA, Elmeshad AN, Fares AR. Enhanced solubility and dissolution rate of lacidipine nanosuspension: formulation via antisolvent sonoprecipitation technique and optimization using Box-Behnken design. AAPS PharmSciTech. 2016;18(4):1–14.Google Scholar
- 33.Weuts I, Van Dycke F, Voorspoels J, De Cort S, Stokbroekx S, Leemans R, et al. Physicochemical properties of the amorphous drug, cast films, and spray dried powders to predict formulation probability of success for solid dispersions: etravirine. J Pharm Sci. 2011;100(1):260–74.CrossRefGoogle Scholar