Academic Journal
Mechanistic evaluation of counterion selection for lipophilic salt enabled lipid based drug delivery: a case study with acalabrutinib.
| Τίτλος: | Mechanistic evaluation of counterion selection for lipophilic salt enabled lipid based drug delivery: a case study with acalabrutinib. |
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| Συγγραφείς: | Debaje S; The Supersaturated Oral Drug Delivery Laboratory (SODDL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India., Guleria K; The Supersaturated Oral Drug Delivery Laboratory (SODDL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India., Sangamwar AT; The Supersaturated Oral Drug Delivery Laboratory (SODDL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India. Electronic address: Abhays@niper.ac.in. |
| Πηγή: | International journal of pharmaceutics [Int J Pharm] 2026 Sep 05; Vol. 702, pp. 127200. Date of Electronic Publication: 2026 Jul 20. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier/North-Holland Biomedical Press Country of Publication: Netherlands NLM ID: 7804127 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3476 (Electronic) Linking ISSN: 03785173 NLM ISO Abbreviation: Int J Pharm Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Amsterdam, Elsevier/North-Holland Biomedical Press. |
| Ιατρικοί όροι (MeSH): | Lipids*/chemistry , Ions*/chemistry , Drug Delivery Systems*, Salts/chemistry ; Drug Compounding ; Solubility |
| Περίληψη: | Poor solubility of highly crystalline drug candidates in lipid vehicles limits the applicability of lipid-based formulations (LBFs), particularly for high-dose "brick dust" molecules. Acalabrutinib represents one such compound, exhibiting high crystallinity and inadequate solubility in lipid vehicles, which consequently restricts achievable drug loading in LBF systems. In this context, lipophilic salt formation represents a promising strategy to enhance lipid solubility and overcome these formulation limitations. Accordingly, the present work investigated a systematic lipophilic salt/complex approach to enhance the drug loading and gastrointestinal solubilization performance of acalabrutinib through rational counterion selection based on acidic headgroup chemistry and alkyl chain length. Nine lipophilic counterions comprising fatty carboxylates, alkyl sulfonates, and alkyl sulfates with caprylyl (C8), lauryl (C12), and stearyl (C18) alkyl chains were comparatively evaluated. Lipophilic salts/complexes were synthesized by a salt metathesis reaction and subsequently characterized using FTIR, 1H NMR, PXRD, DSC and HSM, which collectively indicated stronger ionic association, reduced crystallinity, and greater solid-state modulation in sulfate and sulfonate systems relative to fatty acid complexes. These physicochemical modifications translated into substantial improvements in drug loading within lipid-based formulations, with sulfate and sulfonate salts demonstrating the greatest enhancement, achieving up to 8.45-fold and 8.04-fold increases in MCT- and LCT-based systems, respectively, compared with the free base. During pH-stat in vitro lipolysis, lipophilic salt formulations maintained higher apparent aqueous drug concentrations relative to free base loaded LBFs. Based on the combined in vitro performance, representative stearyl-based long-chain LBFs were comparatively evaluated in vivo, where the acalabrutinib stearyl sulfate system demonstrated superior oral exposure relative to the corresponding counterion systems, crystalline acalabrutinib suspension, and conventional free base LBF. Collectively, these findings demonstrate that rational counterion selection can serve as an effective formulation-oriented strategy to enhance drug loading, digestion-phase solubilization, and oral delivery of brick dust molecules from lipid-based systems. (Copyright © 2026 Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Bioavailability; In-vitro lipolysis; Lipid based formulations; Lipophilic salts; SNEDDS |
| Substance Nomenclature: | 0 (Lipids) 0 (Ions) 0 (Salts) |
| Entry Date(s): | Date Created: 20260720 Date Completed: 20260908 Latest Revision: 20260908 |
| Update Code: | 20260908 |
| DOI: | 10.1016/j.ijpharm.2026.127200 |
| PMID: | 42476275 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1873-3476 |
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| DOI: | 10.1016/j.ijpharm.2026.127200 |