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Risk-Based Predictive Stability (RBPS) tools, such as the Accelerated Stability Assessment Program (ASAP) and other models, are used routinely within pharmaceutical development to quickly assess stability characteristics, especially to understand mechanisms of degradation. These modeling tools provide stability insights within weeks that could take months or years to understand using long-term stability conditions only. Despite their usefulness, the knowledge gained through these tools are not as broadly used to support regulatory filing strategies. This paper aims to communicate how industry has used RBPS data to support regulatory submissions and discuss the regulatory feedback that was received.

In consideration of the recent ICH Quality Discussion Group (QDG) recommended revision to the ICH series of stability guidelines, the IQ Consortium (International Consortium for Innovation and Quality in Pharmaceutical Development) Science- and Risk-based Stability Working Group conducted a comprehensive review of ICH Q1A, Q1B, Q1C, Q1D, Q1E, and Q5C to identify areas where the guidelines could be clarified, updated, and amended to reflect the potential knowledge gained from current risk-based predictive stability tools and to consider other science- and risk-based stability strategies in accordance with ICH Q8-12. The recommendations propose a holistic approach to stability understanding, utilizing historical data, prior knowledge, modeling, and a risk assessment process to expand the concept of what could be included (or would be acceptable) in the core stability data package, including type and amount of stability evidence, assignment of retest period and shelf-life for a new product, and assessment of the impact of post-approval changes.

Spectral comparison is an important part of the assignment of the absolute configuration (AC) by vibrational circular dichroism (VCD), or equally by Raman optical activity (ROA). In order to avoid bias caused by personal interpretation, numerical methods have been developed to compare measured and calculated spectra. Using a neighbourhood similarity measure, the agreement between a computed and measured VCD or ROA spectrum is expressed numerically to introduce a novel confidence level measure. This allows users of vibrational optical activity (VOA) techniques (VCD and ROA) to assess the reliability of their assignment of the AC of a compound. To that end, a database of successful AC determinations is compiled along with neighbourhood similarity values between the experimental spectrum and computed spectra for both enantiomers. For any new AC determination, the neighbourhood similarities between the experimental spectrum and the computed spectra for both enantiomers are projected on the database allowing an interpretation of the reliability of their assignment.

Vibrational modes in an achiral molecule may acquire rotational strength by complexation to a chiral molecule, as happens for achiral solvent molecules complexed to a chiral solute. We investigate this transfer of chirality in vibrational circular dichroism for the pulegone molecule in CDCl3 solvent from the point of view of the robustness concept introduced recently. It turns out that the transfer of chirality yields nonrobust modes, which means that, although they are observed in vibrational circular dichroism (VCD) experiments, the sign of these modes cannot be predicted reliably with standard (Density Functional Theory) VCD calculations. This limits the usefulness of the induced chirality phenomenon for obtaining information on the intermolecular interactions that give rise to it. Chirality 21:E287–E297, 2009. © 2010 Wiley-Liss, Inc.

Product ion distributions (PIDs) for the reactions of seven sesquiterpenes (aromadendrene, β-caryophyllene, α-cedrene, α-humulene, isolongifolene, longifolene and δ-neoclovene) with H 3 O + , NO + and O 2 + reagent ions have been determined in a selected ion flow tube (SIFT) instrument operated at 1.4 mbar and 297 K. The H 3 O + /sesquiterpene reactions mainly proceed by non-dissociative proton transfer (C 15 H 25 + , m / z 205), except for the reactions of H 3 O + with β-caryophyllene and α-humulene which are characterized by more pronounced fragmentation. Two groups of fragment ions of which the components are separated by CH 2 units, are generally observed. The NO + /sesquiterpene reactions mainly result in the charge transfer product (C 15 H 24 + , m / z 204). The NO + /sesquiterpene charge transfer yield is generally larger than the protonated sesquiterpene yield for the corresponding H 3 O + /sesquiterpene reactions. A small amount of association product (C 15 H 24 ·NO + , m / z 234) is found for the sesquiterpenes aromadendrene, β-caryophyllene, longifolene and δ-neoclovene. O 2 + /sesquiterpene reactions are found to proceed mainly by dissociative charge transfer, resulting in severe fragmentation. The collisional rate constants for these reactions were calculated using the parameterized theory of Su and Chesnavich, taking into account polarizabilities and electrical dipole moments of the sesquiterpenes as derived from B3LYP/aug-cc-pVDZ quantum chemical calculations. Experimental rate constants for the reactions of NO + and O 2 + with the sesquiterpenes were obtained relatively to the calculated H 3 O + /sesquiterpene rate constants. Absolute H 3 O + /sesquiterpene rate constants were obtained for β-caryophyllene, α-cedrene, α-humulene and longifolene. Large but systematic discrepancies between experimentally determined rate constants and calculated collision rate constants suggest the need for a re-evaluation of sesquiterpene saturation vapor pressure values. In view of possible detection of sesquiterpenes in moist samples, the influence of water vapor on the ion chemistry was investigated and the reaction rate constants of H 3 O + ·H 2 O and NO + ·H 2 O with sesquiterpenes were obtained relative to those of bare H 3 O + and NO + , respectively.

It is shown how the presence of a chiral compound in solution induces chirality in the surrounding solvent molecules. Using Vibrational Circular Dichroism on camphor dissolved in deuterated chloroform, it is found that the C–D stretch in the latter indeed becomes VCD active. The experimental results agree with ab initio computed spectra for 1:1 associations between the solvent and solute.

The rate constants and product ion distributions of the reactions of H3O+, NO+ and O2 + with 1-penten-3-ol, cis- and trans-2-penten-1-ol, 3-methyl-2-buten-1-ol, 3-methyl-3-buten-1-ol, 2-methyl-3-buten-2-ol, cis- and trans-2-hexen-1-ol, cis- and trans-3-hexen-1-ol, 1-octen-3-ol and 6-methyl-5-hepten-2-ol have been determined at 150 Pa and 295 K using a selected ion flow tube (SIFT). All reactions were found to proceed at a rate close to the collision rate, calculated with the Su and Chesnavich model, using the polarizability and electric dipole moment of the compounds derived from B3LYP/aug-cc-pVDZ quantum chemical calculations. All H3O+ ion/molecule reactions proceed mainly by elimination of a water molecule after protonation. Therefore, the H3O+ precursor ion is not suited to distinguish isomers by the chemical ionization technique in samples, containing several of the C5 (C6 or C8) unsaturated alcohols. The NO+ reactions are generally characterized by several reaction pathways, such as hydride and/or hydroxide ion transfer and/or non-dissociative charge transfer and/or three-body association. The SIFT-MS spectra of the ion/molecule reactions of O2 + with the unsaturated alcohols also show multiple ionic products. Based upon the measured product ion distributions, it can be concluded that in some particular cases the NO+ or O2 + precursor ions are appropriate to identify and quantify isomers in mixtures of the unsaturated alcohols studied. Especially in leaf wounding experiments, during which cis-3-hexen-1-ol and trans-2-hexen-1-ol are emitted, the chemical ionization technique, based upon the NO+ or O2 + precursor ion, may be a valuable diagnostic tool to distinguish and quantify these isomeric forms.

The absolute configurations of four bicylco[3.3.0]octane derivatives: endo -bicyclo[3.3.0]octane-2,6-diol, endo -2,6-diacetoxybicyclo[3.3.0]octane, endo -bicyclo[3.3.0]octane-2,6-dione and bicyclo[3.3.0]octa-2,6-dien-2,6-bistriflate were studied by vibrational circular dichroism (VCD). These chiral derivates are of interest as intermediates in the asymmetric synthesis of enantiomerically pure natural products and chiral ligands for asymmetric catalysis. VCD has been used to determine the absolute configuration of each compound, proving the capability of VCD for molecules with several stereogenic centres. IR and VCD spectra have been simulated at the B3LYP/6-31G ∗ level for all possible diastereomers. Based on the agreement between the experimental and the calculated spectrum, the stereochemistry of each compound could be assigned. The predicted absolute configurations are found to agree with literature data.

The VCD spectra of pulegone, dissolved in CDCl3, CD2Cl2 and CS2 have been recorded in the frequency range from 1000 to 3000 cm(-1). The assignment of the absolute configuration was performed by comparing the experimental data with theoretical spectra computed at the B3LYP/6-311+G(d,p) level. Analysis of the agreement in several spectral regions revealed significant shortcomings when comparing with vacuum calculations. It is shown that the agreement improves when the solvent effects are taken into account by a continuum model. For the measurements in CDCl3 and CD2Cl2 further improvement was found when considering explicitly 1 : 1 complexes between a pulegone and a CDCl3 or CD2Cl2 solvent molecule in vacuo, while the best agreement was obtained when embedding these in a continuum model. The presence of the chiral solute was found to induce a VCD active C-D stretch band which could be modeled also at ab initio level.