A Structured Approach To Cope with Impurities during Industrial Crystallization Development.

The perfect separation with optimal productivity, yield, and purity is very difficult to achieve. Despite its high selectivity, in crystallization unwanted impurities routinely contaminate a crystallization product. Awareness of the mechanism by which the impurity incorporates is key to understanding how to achieve crystals of higher purity. Here, we present a general workflow which can rapidly identify the mechanism of impurity incorporation responsible for poor impurity rejection during a crystallization. A series of four general experiments using standard laboratory instrumentation is required for successful discrimination between incorporation mechanisms. The workflow is demonstrated using four examples of active pharmaceutical ingredients contaminated with structurally related organic impurities. Application of this workflow allows a targeted problem-solving approach to the management of impurities during industrial crystallization development, while also decreasing resources expended on process development.

Recent Advances in Co-processed APIs and Proposals for Enabling Commercialization of These Transformative Technologies.

Optimized physical properties (e.g., bulk, surface/interfacial, and mechanical properties) of active pharmaceutical ingredients (APIs) are key to the successful integration of drug substance and drug product manufacturing, robust drug product manufacturing operations, and ultimately to attaining consistent drug product critical quality attributes. However, an appreciable number of APIs have physical properties that cannot be managed via routes such as form selection, adjustments to the crystallization process parameters, or milling. Approaches to control physical properties in innovative ways offer the possibility of providing additional and unique opportunities to control API physical properties for both batch and continuous drug product manufacturing, ultimately resulting in simplified and more robust pharmaceutical manufacturing processes. Specifically, diverse opportunities to significantly enhance API physical properties are created if allowances are made for generating co-processed APIs by introducing nonactive components (e.g., excipients, additives, carriers) during drug substance manufacturing. The addition of a nonactive coformer during drug substance manufacturing is currently an accepted approach for cocrystals, and it would be beneficial if a similar allowance could be made for other nonactive components with the ability to modify the physical properties of the API. In many cases, co-processed APIs could enable continuous direct compression for small molecules, and longer term, this approach could be leveraged to simplify continuous end-to-end drug substance to drug product manufacturing processes for both small and large molecules. As with any novel technology, the regulatory expectations for co-processed APIs are not yet clearly defined, and this creates challenges for commercial implementation of these technologies by the pharmaceutical industry. The intent of this paper is to highlight the opportunities and growing interest in realizing the benefits of co-processed APIs, exemplified by a body of academic research and industrial examples. This work will highlight reasons why co-processed APIs would best be considered as drug substances from a regulatory perspective and emphasize the areas where regulatory strategies need to be established to allow for commercialization of innovative approaches in this area.

Applications of In Silico Solvent Screening and an Interactive Web-Based Portal for Pharmaceutical Crystallization Process Development.

In an effort to reduce development time and costs associated with active pharmaceutical ingredient process solvent selection and crystallization design, a tiered approach to crystallization solvent selection was developed that leverages different solubility modeling tools selected on the basis of available data and the intended use of the prediction. To facilitate easy access to routine solubility modeling functionality with a high level of automation and parallelization, a web-based in silico solvent-screening tool was also developed as well as a user interface to visualize and interpret the large number of predicted results. Examples are presented to illustrate the utility of the workflow and solvent-screening tool at various stages of development for a diverse range of crystallization processes. Implementation of the in silico solvent selection workflow has led to a ∼10× reduction in active pharmaceutical ingredient usage and 20% reduction in full-time employee time per project based on average after the first year.

Origins of Regioselectivity in the Fischer Indole Synthesis of a Selective Androgen Receptor Modulator.

The selective androgen receptor modulator, (S)-(7-cyano-4-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)carbamic acid isopropyl ester, LY2452473, is a promising treatment of side effects of prostate cancer therapies. An acid-catalyzed Fischer indolization is a central step in its synthesis. The reaction leads to only one of the two possible indole regioisomers, along with minor decomposition products. Computations show that the formation of the observed indole is most favored energetically, while the potential pathway to the minor isomer leads instead to decomposition products. The disfavored [3,3]-sigmatropic rearrangement, which would produce the unobserved indole product, is destabilized by the electron-withdrawing phthalimide substituent. The most favored [3,3]-sigmatropic rearrangement transition state is bimodal, leading to two reaction intermediates from one transition state, which is confirmed by molecular dynamics simulations. Both intermediates can lead to the observed indole product, albeit through different mechanisms.

Salt Stability - The Effect of pHmax on Salt to Free Base Conversion.

PURPOSE: The aim of this study was to investigate how the disproportionation process can be impacted by the properties of the salt, specifically pHmax. METHODS: Five miconazole salts and four sertraline salts were selected for this study. The extent of conversion was quantified using Raman spectroscopy. A mathematical model was utilized to estimate the theoretical amount of conversion. RESULTS: A trend was observed that for a given series of salts of a particular basic compound (both sertraline and miconazole are bases), the extent of disproportionation increases as pHmax decreases. Miconazole phosphate monohydrate and sertraline mesylate, although exhibiting significantly different pHmax values (more than 2 units apart), underwent a similar extent of disproportionation, which may be attributed to the lower buffering capacity of sertraline salts. CONCLUSION: This work shows that the disproportionation tendency can be influenced by pHmax and buffering capacity and thus highlights the importance of selecting the appropriate salt form during the screening process in order to avoid salt-to-free form conversion.

Experimental and theoretical characterization of the 2(2)A'-1(2)A' transition of BeOH/D.

The hydroxides of Ca, Sr, and Ba are known to be linear molecules, while MgOH is quasilinear. High-level ab initio calculations for BeOH predict a bent equilibrium structure with a bond angle of 140.9°, indicating a significant contribution of covalency to the bonding. However, experimental confirmation of the bent structure is lacking. In the present study, we have used laser excitation techniques to observe the 2(2)A'-1(2)A' transition of BeOH/D in the energy range of 30300-32800 cm(-1). Rotationally resolved spectra were obtained, with sufficient resolution to reveal spin splittings for the electronically excited state. Two-color photoionization was used to determine an ionization energy of 66425(10) cm(-1). Ab initio calculations were used to guide the analysis of the spectroscopic data. Multireference configuration interaction calculations were used to construct potential energy surfaces for the 1(2)A', 2(2)A', and 1(2)A" states. The rovibronic eigenstates supported by these surfaces were determined using the Morse oscillator rigid bender internal dynamics Hamiltonian. The theoretical results were in sufficiently good agreement with the experimental data to permit unambiguous assignment. It was confirmed that the equilibrium geometry of the ground state is bent and that the barrier to linearity lies below the zero-point energies for both BeOH and BeOD.

Implementing quality by design in pharmaceutical salt selection: a modeling approach to understanding disproportionation.

PURPOSE: Salts of active pharmaceutical ingredients are often used to enhance solubility, dissolution rate, or take advantage of other improved solid-state properties. The selected form must be maintained during processing and shelf-life to ensure quality. We aimed to develop a model to quantify risk of disproportionation, where the salt dissociates back to the freebase form. METHODS: A mechanistic model based on thermodynamics was built to predict disproportionation. Stress testing of molecules in combination with excipients was used to benchmark model predictions. X-ray powder diffraction and solid-state NMR were used to quantify the formation of freebase experimentally. RESULTS: 13 pharmaceutical compounds were screened in 4 formulations containing different combinations of excipients. The test set spanned molecules which did and did not disproportionate and also formulations which did and did not induce disproportionation. Model predictions were in qualitative agreement with the experimental data, recovering trends of how disproportionation varies with humidity, formulation excipients, base pK(a) and solubility of the API. CONCLUSIONS: The model can predict the balance between different driving forces for disproportionation with limited experimental data resulting in a tool to aid in early-phase risk assessment and formulation design with respect to disproportionation.

Experimental and theoretical studies of the electronic transitions of BeC.

Electronic spectra for BeC have been recorded over the range 30,500-40,000 cm(-1). Laser ablation and jet-cooling techniques were used to obtain rotationally resolved data. The vibronic structure consists of a series of bands with erratic energy spacings. Two-color photoionization threshold measurements were used to show that the majority of these features originated from the ground state zero-point level. The rotational structures were consistent with the bands of (3)Π-X(3)Σ(-) transitions. Theoretical calculations indicate that the erratic vibronic structure results from strong interactions between the four lowest energy (3)Π states. Adiabatic potential energy curves were obtained from dynamically weighted MRCI calculations. Diabatic potentials and coupling matrix elements were then reconstructed from these results, and used to compute the vibronic energy levels for the four interacting (3)Π states. The predictions were sufficiently close to the observed structure to permit partial assignment of the spectra. Bands originating from the low-lying 1(5)Σ(-) state were also identified, yielding a (5)Σ(-) to X(3)Σ(-) energy interval of 2302 ± 80 cm(-1) and molecular constants for the 1(5)Π state. The ionization energy of BeC was found to be 70,779(40) cm(-1).

ReactNMR and ReactIR as reaction monitoring and mechanistic elucidation tools: the NCS mediated cascade reaction of α-thioamides to α-thio-ß-chloroacrylamides.

On-flow ReactIR and (1)H NMR reaction monitoring, coupled with in situ intermediate characterization, was used to aid in the mechanistic elucidation of the N-chlorosuccinimide mediated transformation of an α-thioamide. Multiple intermediates in this reaction cascade are identified and characterized, and in particular, spectroscopic evidence for the intermediacy of the chlorosulfonium ion in the chlorination of α-thioamides is provided. Further to this, solvent effects on the outcome of the transformation are discussed. This work also demonstrates the utility of using a combination of ReactIR and flow NMR reaction monitoring (ReactNMR) for characterizing complex multicomponent reaction mixtures.

Bonding in beryllium clusters.

Beryllium clusters provide an ideal series for exploring the evolution from discrete molecules to the metallic state. The beryllium dimer has a formal bond order of zero, but the molecule is weakly bound. In contrast, bulk-phase beryllium is a hard metal with a high melting point. Theoretical calculations indicate that the bond energies increase dramatically for Be(n) clusters in the range n=2-6. A triplet ground state is found for n=6, indicating an early emergence of metallic properties. There is an extensive body of theoretical work on smaller Be(n) clusters, in part because this light element can be treated using high-level methods. However, the apparent simplicity of beryllium is deceptive, and the calculations have proved to be challenging owing to strong electron correlation and configuration interaction effects. Consequently, these clusters have become benchmark systems for the evaluation of a wide spectrum of quantum chemistry methods.

Experimental and theoretical investigations of rotational energy transfer in HBr + He collisions.

Rotational relaxation rates for HBr(v = 1) colliding with helium atoms at room temperature have been measured using a time-resolved optical-optical double resonance technique. Rotational state selective excitation of v = 1 for rotational levels in the range J = 1-9 was achieved by stimulated Raman pumping. The population decay in the prepared states and the transfer of population to nearby rotational states was monitored via 2 + 1 resonance-enhanced multiphoton ionization (REMPI) spectroscopy using the g(3)Σ(-)-X(1)Σ(+) (0-1) band. Collision-induced population evolution for transfer events with |ΔJ| ≤ 8 was observed at pressures near 0.7 Torr. The experimental data were analyzed using fitting and scaling functions to generate state-to-state rotational energy transfer rate constant matrices. Total depopulation rate constants were found to be in the range (1.3 to 2.0) × 10(-10) cm(3) s(-1). As a test of current computational methods, state-to-state rotational energy transfer rate constants were calculated using ab initio theory. The total removal rate constants were in good agreement with the measured values, but the transfer probabilities for events with |ΔJ| ≥ 3 were underestimated. Inspection of the anisotropic characteristics of the potential energy surface did not yield an obvious explanation for the discrepancies, but it is most likely that the problem stems from inaccuracies in the potential surface.

Spectroscopy, structure, and ionization energy of BeOBe.

Electronic transitions of BeOBe have been investigated using laser-induced fluorescence and resonance enhanced multiphoton ionization techniques in the 27000-33000 cm-1 range. Vibronic progressions observed in these spectra were assigned to the symmetric and antisymmetric stretching vibrations in the excited electronic state. The nuclear spin statistics of the ground state, observed in the intensity patterns of rotationally resolved spectra, confirmed that the molecule is symmetric (BeOBe) and has 1 Sigma(g)+ symmetry. Analysis of the rotational structure yielded a value of 1.396(3) A for the BeO bond length. Ground state vibrational frequencies were determined using stimulated emission pumping. Photoionization efficiency curves were recorded that yielded a value of 8.119(5) eV for the BeOBe ionization energy. Multireference electronic structure calculations have been used to predict molecular constants and explore the orbital compositions of the ground and excited states.

On the ionization energy of HfO.

Using a newly developed relativistic pseudopotential and a series of correlation consistent basis sets for Hf, the ionization energy of HfO and the spectroscopic properties of the HfO(+) cation have been determined in coupled cluster calculations. After accounting for basis set incompleteness, outer-core correlation, the pseudopotential approximation, and higher order electron correlation effects, excellent agreement with recent experimental measurements is obtained.

Study of the CH3 H2O radical complex stabilized in helium nanodroplets.

The weakly bound CH(3)H(2)O radical complex has been investigated by infrared laser spectroscopy. The complex is stabilized in helium nanodroplets and prepared by sequential pick up of a methyl radical and water molecule. Partially rotationally resolved spectra corresponding to the v = 1 <-- 0 excitation of the symmetric H(2)O stretching vibration within the complex show a significant red shift (25.06 cm(-1)) when compared with the symmetric stretch of H(2)O monomer, in agreement with the hydrogen bonded like structure derived by theory. Additional broad features were observed in the region predicted by theory for the antisymmetric stretch supporting our assignment. The B rotational constant is found to be 3.03 times smaller than predicted by ab initio calculations, with the reduction being attributed to the effects of helium solvation. The permanent electric dipole moment of the complex is experimentally determined to be 2.1 +/- 0.3 D using Stark spectroscopy. Ab initio calculations are also reported that provide support to the experimental results, as well as investigate the nature of large amplitude vibrational motion within the complex.

Beryllium dimer--caught in the act of bonding.

The beryllium dimer is a deceptively simple molecule that, in spite of having only eight electrons, poses difficult challenges for ab initio quantum chemical methods. More than 100 theoretical investigations of the beryllium dimer have been published, reporting a wide range of bond lengths and dissociation energies. In contrast, there have been only a handful of experimental studies that provide data against which these models could be tested. Ultimately, the uncertain extrapolation behavior associated with the available data has prevented quantitative comparisons with theory. In our experiment, we resolve this issue by recording and analyzing spectra that sample all the bound vibrational levels of the beryllium dimer molecule's electronic ground state. After more than 70 years of research on this problem, the experimental data and theoretical models for the dimer are finally reconciled.

Ionization energy measurements and spectroscopy of HfO and HfO+.

Rotationally resolved spectra for the HfO(+) cation have been recorded using the pulsed field ionization zero electron kinetic energy (PFI-ZEKE) technique. Resonant excitation of the F(0(+))<--X (1)Sigma(+) band system of HfO was used as an intermediate level providing molecule and rovibrational state selectivity in the ionization process. The ionization energy (IE) of HfO, derived from the PFI-ZEKE spectrum, was determined to be 7.916 87(10) eV, which is 0.37 eV higher than the value reported from electron impact measurements. Underestimation of the IE in the previous studies is attributed to ionization of thermally excited states. A progression in the HfO(+) stretch vibration up to nu(+)=4 was observed in the PFI-ZEKE spectrum, allowing for the determination of the ground electronic state vibrational frequency of omega(e)(+)=1017.7(10) cm(-1) and anharmonicity of omega(e)x(e)(+)=3.2(2) cm(-1). The rotational constant of HfO(+) was determined to be 0.403(5) cm(-1). Benchmark theoretical ab initio calculations were carried out in order to explore the effects of electron correlation on the predicted molecular properties. Survey scans utilizing laser induced fluorescence and resonance enhanced multiphoton ionization detection revealed many previously unassigned bands in the region of the F-X and G-X bands of HfO, which we attribute to nominally forbidden singlet-triplet transitions of HfO.

Experimental and theoretical study of the electronic spectrum of BeAl.

The electronic structure of BeAl was investigated by laser induced fluorescence and resonance enhanced multiphoton ionization spectroscopy. BeAl was formed by pulsed laser ablation of a Be/Al alloy in the presence of helium carrier gas, followed by a free jet expansion into vacuum. In agreement with recent ab initio studies, the molecule was found to have a (2)Pi(1/2) ground state. Transitions to two low lying electronic states, (2)2Pi1/2(v') <-- X 2Pi1/2 (v'' = 0) and (1)2Delta(v') <-- X 2Pi1/2 (v'' = 0,1), were observed and rotationally analyzed. An additional band system, identified as (4)2Sigma+(v') <-- X 2Pi1/2, was found in the 28 000-30 100 cm(-1) energy range. This transition exhibited an unusual pattern of vibrational levels resulting from an avoided crossing with the (5)2Sigma+ electronic state. New multi-reference configuration interaction calculations were carried out to facilitate the interpretation of the UV bands. An ionization energy of 48 124(80) cm(-1) was determined for BeAl from photoionization efficiency (PIE) measurements. Fine structure in the PIE curve was attributed to resonances with Rydberg series correlating with vibrationally excited states of the BeAl+ ion. Analysis of this structure yielded a vibrational frequency of 240(20) cm(-1) for the cation.

The ionization energy of Be2, and spectroscopic characterization of the (1)3Sigmau+, (2)3Pig, and (3)3Pig states.

Low lying electronic states of the beryllium dimer were investigated by laser induced fluorescence (LIF) and resonance enhanced multiphoton ionization (REMPI) techniques. Be(2) was formed by pulsed laser ablation of Be metal in the presence of helium carrier gas, followed by a free jet expansion into vacuum. Several previously unobserved states of the dimer were characterized. These included transitions of the triplet manifold (2)(3)Pi(g) <-- (1)(3)Sigma(u)+ and (3)(3)Pi(g) <-- (1)(3)Sigma(u)+, for which rotationally resolved bands were obtained. In addition, transitions to the v' = 10-18 vibrational levels of the A (1)Pi(u) state were recorded. Photoionization efficiency (PIE) measurements were used to determine an accurate ionization energy (IE) for Be(2) of 7.418(5) eV and the term energy for (1)(3)Sigma(u)+. Above the ionization threshold the PIE spectrum was found to be highly structured, consisting of overlapping Rydberg series that converged on excited vibrational levels of Be(2)+. Analysis of these series yielded a vibration frequency for the X(2)Sigma(u)+ state of 498(20) cm(-1). The bond dissociation energy for Be(2)+, deduced from the IE measurement, was 16 072(40) cm(-1). Multi-reference configuration interaction (MRCI) calculations were carried out for Be(2) and Be(2)+, yielding results that were in excellent agreement with the experimental observations.

Spectroscopy of the UO+2 cation and the delayed ionization of UO2.

Vibronically resolved spectra for the UO+2 cation have been recorded using the pulsed field ionization zero electron kinetic energy (PFI-ZEKE) technique. For the ground state, long progressions in both the bending and symmetric stretch vibrations were observed. Bend and stretch progressions of the first electronically excited state were also observed, and the origin was found at an energy of 2678 cm(-1) above the ground state zero-point level. This observation is consistent with a recent theoretical prediction [Infante et al., J. Chem. Phys. 127, 124308 (2007)]. The ionization energy for UO2, derived from the PFI-ZEKE spectrum, namely, 6.127(1) eV, is in excellent agreement with the value obtained from an earlier photoionization efficiency measurement. Delayed ionization of UO2 in the gas phase has been reported previously [Han et al., J. Chem. Phys. 120, 5155 (2004)]. Here, we extend the characterization of the delayed ionization process by performing a quantitative study of the ionization rate as a function of the energy above the ionization threshold. The ionization rate was found to be 5 x 10(6) s(-1) at threshold, and increased linearly with increasing energy in the range investigated (0-1200 cm(-1)).