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.
Three crystal structures of donepezil salts formed with sulfonic acids were obtained. Interestingly, donepezil-besylate and donepezil-tosylate share similar crystal molecular conformations and crystal packing. On the basis of PXRD patterns, donepezil-mesylate and donepezil-esylate are likely to share similar crystal structures. The sulfonyl hydroxides of all three sulfonic acids form an intermolecular hydrogen bond with the piperidyl amine of donepezil. Solid state characterization showed that the T g 's of all four amorphous donepezil salts are similar to each other and increase significantly compared to T g of donepezil. Stability analysis found that the amorphous salts of donepezil formed with mesylate and esylate led to significantly improved physical stability under accelerated stability conditions, but the other donepezil-sulfonic acid salts did not. Solubility data showed that mesylate/esylate salts of donepezil significantly increase the solubility of donepezil that is not shown by other salt forms. Solubility analysis indicated that the solubility of donepezil-mesylate and donepezil-esylate is extremely high compared to that of donepezil-besylate and donepezil-tosylate. We concluded that the extremely high solubility is responsible for delaying the rate of nucleation and thus improving the physical stability of amorphous donepezil. This study highlights that the aqueous solubility of amorphous material is an important factor when considering the physical stability of amorphous material under high relative humidity.
Eight donepezil multicomponent systemssix new multicomponent systems (donepezil–mandelic acid, donepezil–mandelic acid–water, donepezil–water–maleic acid, donepezil–fumaric acid, donepezil–benzenesulfonic acid–water, and donepezil 3.5 hydrate) and two known multicomponent systems (donepezil–benzenesulfonic acid and donepezil–oxalic acid–water)were investigated in the present study. A detailed structural and spectroscopic analysis of the donepezil multicomponent systems was conducted to determine which interactions are involved and which class each system belongs to. It was found that various interactions, such as cation–anion, water–cation, water–anion, hydrogen-bond, and water–water interactions, were present in these systems. In addition, an interesting donepezil–maleic acid multicomponent system that only exists in an amorphous form in the absence of water was discovered. Water is necessary to bridge the donepezil molecules with the maleic acid molecules in the crystalline state; therefore, no acid–base interaction is observed in the system. This type of interaction is difficult to identify without single-crystal X-ray analysis. This donepezil–maleic acid multicomponent system is neither a salt nor a cocrystal system, even though the system includes basic drug and acid components, but may represent a donepezil multicomponent hydrate. This study illustrates the importance of detailed analysis to determine the interactions present within multicomponent systems and demonstrates the interesting multicomponent hydrate system.
In dem vorgeschlagenen Potentialmodell für polare Moleküle werden die Mole".‐ küle als harte Kugeln mit gleichmäßig verteilten Punktdipolen angenommen.
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