New Category for Active Pharmaceutical Ingredients, a Low Molecular Weight Organogelator: Crystal Structure of Atorvastatin Calcium and Its Unusual Phase Transition Behavior during Dissolution

Abstract

A gel is presented which represents a new category of pharmaceutical active ingredient in addition to the conventional crystalline and amorphous forms. The crystal structure of atorvastatin calcium ethylene glycol solvate suggests atorvastatin calcium to be a low-molecular weight organogelator that forms organogels with a wide variety of alkyl alcohols. Metal ion driven ionic interactions based on the amphiphilic nature of atorvastatin calcium leads to a lamellar type packing structure. Like ethylene glycol in its solvated form, alkyl alcohols, ranging from ethanol to octanol, can interact with the metal ions, and/or occupy the void spaces within that lamellar structure, thereby forming organogels featuring highly varying solubilities and unusual phase transition behaviors. An in situ dissolution study identified changes in the amounts/ratios of solvents in the atorvastatin calcium organogels without any significant structural changes, indicating that simultaneous solvent exchange is the mechanism of phase transition during dissolution. The presented low molecular gelator system may also be observed with the other statins that share common structural features with atorvastatin calcium as well as with other pharmaceutical materials. Thus, we propose a new form of active pharmaceutical ingredient, a gel. Since gels show important pharmaceutical properties quite distinct from those of crystalline or amorphous forms, they deserve special attention.

Physicochemical Characterization of a Co-Amorphous Atorvastatin-Irbesartan System with a Potential Application in Fixed-Dose Combination Therapy

“…The initial structures of IRB and ATR to generate the ATR-IRB complexes were taken from the Cambridge Structural Database (CCDC), structure NOZWII for IRB [ 42 ], and structure IZOQIZ for ATR [ 43 ]. For quantum-mechanics calculations, the density functional theory (DFT) formalism was applied [ 44 ].…”

Structural characterization, gelation ability, and energy-framework analysis of two bis(long-chain ester)-substituted 4,4′-biphenyl compounds

“…Gel formation requires that the dissolved gelator selfassemble into a three-dimensional network structure incorporating solvent via noncovalent interactions rather than selfassembly followed by crystallization. As a result, there are few examples of single-crystal structure determinations of gelators (Adhikari et al, 2016;Rojek et al, 2015;Cui et al, 2010;Martin et al, 2016;Geiger et al, 2017). In this article, we report the synthesis and structural characterization of two similar ISSN 2053ISSN -2296 # 2017 International Union of Crystallography compounds with a biphenyl core and long-chain ester substitutents, namely 4,4 0 -bis [5-(methoxycarbonyl)pentyloxy]biphenyl, BBO6-Me, and 4,4 0 -bis [5-(ethoxycarbonyl)pentyloxy]biphenyl, BBO6-Et.…”

Synthesis and characterization of a novel long-alkyl-chain ester-substituted benzimidazole gelator and its octan-1-ol solvate

“…The aggregation behavior of (3) has been explored spectroscopically and the octan-1-ol monosolvate, (4) (Scheme 1), of this novel compound has been structurally characterized by X-ray diffraction. Our results provide a rare example of a gelator that has been characterized by single-crystal X-ray crystallography (Adhikari et al, 2016;Rojek et al, 2015;Cui et al, 2010) and so provide insight into the gelation driving force for this and similar compounds.…”