betadex and 2-phenylphenol

Cyclodextrins are capable to solubilise lipophilic drugs via (partial) inclusion in their lipophilic cavity. This, however, also provides the potential for the extraction of small molecules from production materials. In the present study, the potency of the commercially available and used cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) to extract the preservative 2-phenylphenol (2-PP) from platinum cured silicone tubing was tested. The presence of 2-PP was structurally confirmed with HPLC-UV and LC/MS/MS in HPbetaCD solutions after incubation with platinum cured silicone tubing. HPbetaCD concentration and prior tubing sterilisation were found not to influence the levels of 2-PP extracted. Interestingly, extraction to ethanol was 15-fold higher than observed for HPbetaCD solutions. 2-PP was extracted from silicone tubing during routine manufacture of a blank dosage form formulated with only HPbetaCD, resulting in detectable levels of 2-PP in the final product. In a freeze-dried dosage form containing HPbetaCD and an active pharmaceutical ingredient (exhibiting a stability constant for HPbetaCD/drug of 1045 L/mol), on the other hand, 2-PP was undetectable.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins; Biphenyl Compounds; Chromatography, High Pressure Liquid; Cyclodextrins; Ethanol; Mass Spectrometry; Phase Transition; Preservatives, Pharmaceutical; Silicones; Technology, Pharmaceutical

The formation of inclusion complexes with beta-cyclodextrin was studied for several popular fungicides of different types: prochloraz, 2-phenylphenol, thiophanate methyl, 8-hydroxyquinoline, and benalaxyl. Phase solubility diagrams showed that in all cases complexation takes place, leading to an important increase of water solubility in prochloraz and benalaxyl. Equilibrium association constants could be determined from the phase solubility data and from NMR titrations in the case of 2-phenylphenol. Because of the low solubility of the complex formed between 8-hydroxyquinoline and beta-cyclodextrin, the corresponding association constant could not be determined. The solid complexes of fungicide-cyclodextrin were prepared and isolated by different methods. The isolation of real complexes and not physical mixtures was confirmed in the cases of prochloraz, 2-phenylphenol, and benalaxyl by differential scanning calorimetry.

Topics: Alanine; beta-Cyclodextrins; Biphenyl Compounds; Chemical Phenomena; Chemistry, Physical; Cyclodextrins; Fungicides, Industrial; Imidazoles; Magnetic Resonance Spectroscopy; Solubility

During a compatibility study between a formulation containing sulfobutylether cyclodextrin (SBECD) and silicone tubing, an extraneous peak was observed in the HPLC chromatograms. The extraneous material was identified by LC/MS, MS/MS and UV as a previously unreported tubing extractable, o-phenylphenol (o-PP). Several studies were conducted to assess the impact of formulation and process-related variables on the amount of the o-PP extracted, including contact time, sulfobutylether cyclodextrin concentration, formulation pH, and tubing sterilization and storage conditions. Results show that the concentration of the SBECD, tubing processing and storage conditions and the duration of the study influenced the levels of o-PP extracted. However, the largest contributor to the amount extracted was the lot of tubing tested. The extracted levels varied widely from lot to lot (0.007-3.89microg/cm(2) of tubing surface area). A dynamic study conducted to simulate a manufacturing process also resulted in the extraction of o-PP by the formulation.

Topics: beta-Cyclodextrins; Biphenyl Compounds; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Cyclodextrins; Dose-Response Relationship, Drug; Electrophoresis, Capillary; Ethers; Mass Spectrometry; Pharmacokinetics; Spectrophotometry, Ultraviolet; Sterilization; Time Factors