Hot liquid extrusion assisted drug-cyclodextrin complexation: a novel continuous manufacturing method for solubility and
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ORIGINAL ARTICLE
Hot liquid extrusion assisted drug-cyclodextrin complexation: a novel continuous manufacturing method for solubility and bioavailability enhancement of drugs Alekhya Sri Nagini Manne 1 & Aswathi R Hegde 1 & Sushil Yadaorao Raut 1,2 & Rajat Radhakrishna Rao 1,2 & Vijay Induvadan Kulkarni 2 & Srinivas Mutalik 1 Accepted: 7 September 2020 # The Author(s) 2020
Abstract In this study, drug-cyclodextrin (CD) complexes were prepared using hot liquid extrusion (HLE) process with an aim to improve solubility and bioavailability of carbamazepine. Saturation solubility studies of CBZ in water and different pH media showed a pH-independent solubility. Phase solubility studies of CBZ at different molar concentrations of beta-cyclodextrin (β-CD) and hydroxypropyl beta-cyclodextrin (HP-β-CD) indicated AL-type solubility profile with stability constants of 574 M−1 and 899 M−1 for β-CD and HP-β-CD. Drug-β-CD and drug-HP-β-CD complexes were prepared using HLE process and conventional methods (such as physical mixture, kneading method, and solvent evaporation) as well. Optimized complexes prepared using HLE viz. CBP-4 and CHP-2 showed a solubility of 4.27 ± 0.09 mg/mL and 6.39 ± 0.09 mg/mL as compared to plain CBZ (0.140 ± 0.007 mg/mL). Formation of drug-CD inclusion complexes was confirmed using DSC, FTIR, and XRD studies. Drug release studies indicated highest release of CBZ from CHP-2 (98.69 ± 2.96%) compared to CBP-4 (82.64 ± 2.45%) and plain drug (13.47 ± 0.54%). Complexes prepared using kneading showed significantly lesser drug release (KMB 75.52 ± 2.68% and KMH 85.59 ± 2.80%) as that of CHP-2 and CBP-4. Pre-clinical pharmacokinetic studies in Wistar rats indicated a significant increase in Cmax, Tmax, AUC, and mean residence time for CHP-2 compared to KMH and plain CBZ. All these results suggest that HLE is an effective method to increase the solubility of poorly water-soluble drugs. Keywords Hot liquid extrusion . Carbamazepine . Cyclodextrin . Dissolution . Pharmacokinetics
Introduction Excessive discharge of electrical impulses in a group of brain cells leads to a neurological dysfunction, commonly called as seizures. Seizure episodes can range from a momentary lapse of attention to more severe prolonged convulsions. Recurrent unprovoked seizures or epilepsy is indicative of an underlying Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13346-020-00854-w) contains supplementary material, which is available to authorized users. * Srinivas Mutalik [email protected] 1
Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
2
STEER Life India Private Limited, No. 290, 4th Main, 4th Phase, Peenya Industrial Area, Bangalore 560058, Karnataka, India
brain dysfunction. Epilepsy is a chronic disorder which may affect a part or the entire body and is generally accompanied by loss of cognition [1]. It is a common neurological condition that is prevalent in ~ 50 million people
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