Non-aqueous co-solvent systems have been evaluated for their potential use in the freeze-drying of pharmaceutical products. The advantages of using these non-aqueous solvent systems include: increased drug wetting or solubility, increased sublimation rates, increased pre-dried bulk solution or dried product stability, decreased reconstitution time, and enhancement of sterility assurance of the pre-dried bulk solution. Conversely, the potential disadvantages and issues which must be evaluated include: the proper safe handling and storage of flammable and/or explosive solvents, the special facilities or equipment which may be required, the control of residual solvent levels, the toxicity of the remaining solvent, qualification of an appropriate GMP purity, the overall cost benefit to use of the solvent, and the potential increased regulatory scrutiny. The co-solvent system that has been most extensively evaluated was the tert-butanol/water combination. The tert-butanol possesses a high vapor pressure, freezes completely in most commercial freeze-dryers, readily sublimes during primary drying, can increase sublimation rates, and has low toxicity. This co-solvent system has been used in the manufacture of a marketed injectable pharmaceutical product. When using this solvent system, both formulation and process control required optimization to maximize drying rates and to minimize residual solvent levels at the end of drying. Other co-solvent systems which do not freeze completely in commercial freeze-dryers were more difficult to use and often resulted in unacceptable freeze-dried cakes. Their use appears limited to levels of not more than 10%.

AbstractDie säurekatalysierte Hydrolyse der Titelverbindungen (I) zu den Diolen (II) und Acetaldehyd (III) wird durch den Zusatz von Alkali‐ oder Erdalkalimetallchloriden leicht beschleunigt oder ‐ von (Ib) an ‐ bei zueinander passender Ringund Ionengröße verzögert.

The rate of hydrogen ion-catalysed hydrolysis of crown ether acetals in 60 : 40 (v/v) dioxan–water is found to be strongly decreased by the addition of alkali and alkaline earth metal chlorides having cations of appropriate size to be complexed by the substrate ring. The compounds studied are the monoacetals CH3[graphic omitted] with x= 1–8. The dependence of the initial rate of formation of acetaldehyde on metal-ion concentration is expressed in terms of (i) the equilibrium constant for complex formation, (ii) the influence of the bound cation on the rate constant, and (iii) an electrolyte effect. A curve-fitting procedure is used to derive the parameters governing the first two of these effects. The equilibrium constants are large and cannot be evaluated with any precision, but a fair estimate of the influence of the guest cation on the rate can be obtained. This effect is explicable by the electrostatic repulsion between the cationic charges of the metal ion and the proton added to the acetal in the first step of the hydrolysis. The size of the effect requires the values of the effective relative permittivity of the space between the charges to be close to that of the bulk solvent.

The rate of hydrogen ion-catalysed hydrolysis of crown ether acetals (1) is decreased on complexing of alkali metal cations, whereas a rate increase is correspondingly observed for the reaction of a crown ether ester (2) with hydroxide ions; both effects are semi-quantitatively intelligible on a simple electrostatic model and require the relative permittivity relevant to the interaction of the charges to be that of the bulk solvent.

Under flash vacuum pyrolysis, dioxabicyclo[n.2.1]alkanes (n= 3,4, and 5) isomerise to keto-aldehydes, MeCO[CH2]nCHO, whereas dioxabicyclo[n.2.2]alkanes (n= 2,3, and 4) fragment ot give, by loss of hydrogen and ethylene, mixtures of cycloalkane-1,4-diones and dialdehydes, OHC[CH2]nCHO.

Bulletin des Sociétés Chimiques BelgesVolume 91, Issue 5 p. 483-483 Article The Hydrolysis of Crown Ether-Like Substrates with Hydrolysable Rings: The Effect of Cation Binding on Equilibrium and Rate Constants D. S. Baker, D. S. Baker Department of Chemistry, King's College London, Strand, London WC2R 2LSSearch for more papers by this authorV. Gold, V. Gold Department of Chemistry, King's College London, Strand, London WC2R 2LSSearch for more papers by this authorC. M. Sghibartz, C. M. Sghibartz Department of Chemistry, King's College London, Strand, London WC2R 2LSSearch for more papers by this author D. S. Baker, D. S. Baker Department of Chemistry, King's College London, Strand, London WC2R 2LSSearch for more papers by this authorV. Gold, V. Gold Department of Chemistry, King's College London, Strand, London WC2R 2LSSearch for more papers by this authorC. M. Sghibartz, C. M. Sghibartz Department of Chemistry, King's College London, Strand, London WC2R 2LSSearch for more papers by this author First published: 1982 https://doi.org/10.1002/bscb.198209105142AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume91, Issue51982Pages 483-483 RelatedInformation