Stoichiometric and Nonstoichiometric Hydrates of BrucineClick to copy article linkArticle link copied!
Abstract
The complex interplay of temperature and water activity (aw)/relative humidity (RH) on the solid form stability and transformation pathways of three hydrates (HyA, HyB, and HyC), an isostructural dehydrate (HyAdehy), an anhydrate (AH), and amorphous brucine has been elucidated and the transformation enthalpies quantified. The dihydrate (HyA) shows a nonstoichiometric (de)hydration behavior at RH < 40% at 25 °C, and the removal of the water molecules results in an isomorphic dehydrate structure. The metastable dehydration product converts to AH upon storage at the driest conditions or to HyA if exposed to moisture. HyB is a stoichiometric tetrahydrate. The loss of the water molecules causes HyB to collapse to an amorphous phase. Amorphous brucine transforms to AH at RH < 40% RH and a mixture of hydrated phases at higher RH values. The third hydrate (HyC) is only stable at RH ≥ 55% at 25 °C and contains 3.65–3.85 mol equiv of water. Dehydration of HyC occurs in one step at RH < 55% at 25 °C or upon heating, and AH is obtained. The AH is the thermodynamically most stable phase of brucine at RH < 40% at 25 °C. Depending on the conditions, temperature, and aw, each of the three hydrates becomes the thermodynamically most stable form. This study demonstrates the importance of applying complementary analytical techniques and appropriate approaches for understanding the stability ranges and transition behavior between the solid forms of compounds with multiple hydrates.
Synopsis
Complementary analytical techniques were applied to unravel the complex interplay of temperature and water activity/relative humidity on the solid form stability and transformation pathways of practically relevant forms of brucine. Depending on the environmental conditions, three hydrates (stoichiometric and nonstoichiometric) or anhydrous brucine may become the thermodynamically most stable form. The transformation enthalpies between the solid forms were determined.
1 Introduction
Figure 1
Figure 1. Molecular diagram of brucine (2,3-dimethoxystrychnidin-10-one).
2 Materials and Methods
2.1 Materials
2.2 Gravimetric Moisture Sorption/Desorption Experiments
2.3 Determination of the Critical Water Activity (Slurry Method)
2.4 Temperature-Dependent Slurry Experiments in Water
2.5 Powder X-ray Diffraction (PXRD)
2.6 Thermal Analysis
2.6.1 Differential Scanning Calorimetry (DSC)
2.6.2 Thermogravimetric Analysis (TGA)
2.7 Isothermal Calorimetry (IC)
2.8 FT-Raman Spectroscopy
3 Results and Discussion
3.1 Moisture-Dependent Stability of Brucine Hydrates
3.1.1 Hydrate A
Figure 2
Figure 2. (a) Gravimetric moisture sorption and desorption curves of brucine HyA at 25 °C. Note that measurement points from sorption and desorption cycles coincide. (b) Fractional occupancies of water molecules derived from Rietveld refinements of the PXRD patterns recorded at different RH values. (c) Void space analysis of HyA (CIKDOQ (59)), excluding the water molecules, showing the water channels along the crystallographic b axis. Water space was calculated using the Hydrate Analyzer tool in Mercury and a probe radius and approximately a grid spacing of 1.2 and 0.15 Å, respectively.
Figure 3
Figure 3. (a) Moisture-dependent PXRD measurements of HyA. Numbers on the y axis indicate the moisture in % at which the powder pattern was recorded. (b) Packing diagrams of HyA highlighting the water oxygen positions (W1–W4) at different HyA hydration states. Fractions correspond to water occupancies and were derived from Rietveld refinements (Table S5 of the Supporting Information). For clarity, water hydrogen atoms are omitted in (b).
3.1.2 Hydrate B
Figure 4
Figure 4. (a) Gravimetric moisture sorption and desorption curves of HyB/amorphous brucine at 25 °C. (b) Moisture-dependent PXRD measurements starting from HyB. Numbers on the y axis indicate the moisture in % at which the powder pattern was recorded. Dotted lines in (b) indicate the presence of other not further characterized phase(s). B and C denote characteristic low-angle reflections of HyB and HyC, respectively.
3.1.3 Hydrate C
Figure 5
Figure 5. (a) Gravimetric moisture sorption and desorption curves of brucine HyC ↔ AH at 25 °C. (b) Moisture-dependent PXRD measurements of HyC. Numbers on the y axis indicate the moisture in % at which the powder pattern was recorded. Due to different equilibration times and other parameters such as sample amount, dynamics of the atmosphere, etc., the hydration rates in the gravimetric moisture chamber (GMS) are different from kinetics in the moisture stage (VGI) used for the PXRD recordings.
3.2 Water Diffusion in HyA Monitored Using H/D Exchange
Figure 6
Figure 6. Raman spectra of brucine HyA as a function of time exposure to D2O vapor (∼98% RH). Peaks due to O–D stretching vibrations emerge over the course of a few hours and are highlighted in yellow.
3.3 Determination of the Critical Water Activity (Slurry Method) and Long-Time Stability Experiments
Figure 7
Figure 7. Phase diagram after equilibration for 1 week showing the dependence of brucine solid forms on water activity/relative humidity at 10, 25, and 40 °C.
starting form(s)a | RH/% | after 6 monthsa,b |
---|---|---|
amorphous | ≤31 | AH |
HyAdehy | ≤31 | HyA + AH |
AH | ≤31 | AH |
AH | 43 | AH ≫ HyA |
HyA | 43 | HyA |
HyA + HyB | 43 | HyA > HyB |
HyA + HyC | 43 | HyA + AH |
HyC | 43 | AH ≫ HyAc |
AH | 52 | AH + HyA |
HyA | 52 | HyA |
HyB | 52 | HyB + HyA |
HyC | 52 | AH + HyAc |
AH + HyA | 75 | HyA |
amorphous | 75 | HyA |
HyA + HyB | 75 | HyA |
HyA + HyC | 75 | HyA > HyC |
AH | 92 | HyC |
amorphous | 92 | HyC + HyB ≫ unknown |
HyA + HyB | 92 | HyA + HyB + HyC |
HyC | 92 | HyC |
HyA | 98 | HyA ≫ HyC |
HyB | 98 | HyB ≫ Hy |
AH - anhydrate; HyA - hydrate A (dihydrate); HyB - hydrate B (tetrahydrate); HyC - hydrate C (3.85-hydrate); HyAdehy - isomorphous HyA dehydrate.
Quantified using PXRD: x ≫ y - less than 5% y; x > y - less than 20% y; x + y - similar amounts or ± 20%.
Transformation to HyA via AH.
3.4 Temperature-Dependent Stability of Brucine Hydrates
3.4.1 Hydrate A
Figure 8
Figure 8. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of HyA. The TGA curve (i) was recorded in a pan covered with a one pinhole lid at a heating rate of 5 °C min–1. The DSC curves were recorded in pans with five pinhole lids and heating rates of 3 °C min–1 (ii) and 5 °C min–1 (iii and v), respectively, or a sealed pan (iv, v) at a heating rate of 5 °C min–1. (v) DSC curve of AH.
3.4.2 Hydrate B
Figure 9
Figure 9. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of HyB. The TGA curve (i) was recorded in an open pan at a heating rate of 5 °C min–1. The DSC curves were recorded in open pans at heating rates of 2 °C min–1 (ii) and 5 °C min–1 (iii), respectively, or a sealed pan (iv, v), at a heating rate of 5 °C min–1. (v) DSC curve of amorphous brucine. Dashed ellipsoids in (ii, iii, and v) indicate the glass transition.
3.4.3 Hydrate C
Figure 10
Figure 10. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of HyC. The TGA curve (i) was recorded in a pan covered with a one pinhole lid at a heating rate of 5 °C min–1. The DSC curves were recorded in pans with five (ii) or one (iii) pinhole lids and heating rates of 2 °C min–1 (ii) and 5 °C min–1 (iii and v), respectively, or a sealed pan (iv, v) at a heating rate of 5 °C min–1. (v) DSC curve of AH.
3.5 Thermodynamic Stability and Heat of Transformations

phase | Tfus/°C | ΔfusH/kJ mol–1 | Ttrs/°C | ΔtrsH/kJ mol–1 | phase after transformation | methodg |
---|---|---|---|---|---|---|
AH | 178.9 ± 0.1 | 28.4 ± 0.1 | melt | DSC | ||
HyA | 121.5 ± 1.0 | 31.4 ± 0.8 | 3.0 ± 0.8a | AH | DSC (closed) | |
HyA | ca. 110 | 28.3 ± 0.7 | amorp. + AH (traces) | DSC (open) | ||
amorph. + AH (traces) | ca. 135 | –25.9 ± 0.3 | AH | DSC (open) | ||
HyA | 2.4 ± 0.8b | AH | DSC (open) | |||
HyA | 25 | 5.3 ± 0.9 | HyAdehy | RH-Perf | ||
AHdehy | –2.9 ± 1.2c | AH | DSC + RH-Perf | |||
HyB | 68.9 ± 0.5 | 22.6 ± 0.1 | HyA | DSC (closed) | ||
HyB | ca. 60 | 22.9 ± 1.2d | AH | DSC (open) | ||
HyC | 86.4 ± 0.9 | 21.8 ± 0.6 | HyA | DSC (closed) | ||
HyC | ca. 60 | 20.0 ± 1.4 | AH | DSC (open) | ||
HyC | 25 | 19.2 ± 0.4 | AH | RH-Perf | ||
HyB | 0.8 ± 0.6e | HyC | DSC (closed) | |||
HyB | 3.6 ± 1.3f | HyC | DSC + RH-Perf |
ΔfusH(HyA) – ΔfusH(AH).
ΔtrsH(HyA-amorphous) + ΔtrsH(amorphous-AH).
–ΔtrsH(HyA-HyAdehy) + ΔtrsH(HyA-AH).
ΔtrsH(HyB-amorphous) + ΔtrsH(amorphous-AH).
ΔtrsH(HyB-HyA) – ΔtrsH(HyC-HyA).
ΔtrsH(HyB-AH) – ΔtrsH(HyC-AH).
DSC - differential scanning calorimetry; open - open DSC pan or covered with pinhole lid; closed - closed or high pressure DSC pan; RH-Perf - isothermal calorimetry with the aid of an RH-perfusion cell.

4 Conclusions
Figure 11
Figure 11. Flowcharts showing the dehydration (a), hydration (b), and interrelation pathways of brucine solid forms upon storage.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b01231.
Crystallographic information (list of CSD structures), determination of critical water activity (slurry method), temperature-dependent slurry experiments in water, variable relative humidity PXRD experiments, variable temperature spectroscopy, RH-perfusion isothermal calorimetry (PDF)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Acknowledgment
The authors are grateful to Danya Spechtenhauser for experimental assistance. D.E.B. gratefully acknowledges funding by the Elise Richter Programme of the Austrian Science Fund (FWF, project V436-N34).
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- 21Braun, D. E.; Koztecki, L. H.; McMahon, J. A.; Price, S. L.; Reutzel-Edens, S. M. Mol. Pharmaceutics 2015, 12, 3069– 3088 DOI: 10.1021/acs.molpharmaceut.5b00357Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVShtLrM&md5=03aa5a9f0b1132241db993afd8d16e81Navigating the Waters of Unconventional Crystalline HydratesBraun, Doris E.; Koztecki, Lien H.; McMahon, Jennifer A.; Price, Sarah L.; Reutzel-Edens, Susan M.Molecular Pharmaceutics (2015), 12 (8), 3069-3088CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Elucidating the crystal structures, transformations, and thermodn. of the two zwitterionic hydrates (Hy2 and HyA) of 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoicacid(DB7) rationalizes the complex interplay of temp., water activity, and pH on the solid form stability and transformation pathways to three neutral anhydrate polymorphs (Forms I, II°, and III). HyA contains 1.29 to 1.95 mols. of water per DB7 zwitterion (DB7z). Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°. Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions. X-ray crystallog., solid state NMR, and H/D exchange expts. on highly cryst. phase pure samples obtained by exquisite control over crystn., filtration, and drying conditions, along with computational modeling, provided a mol. level understanding of this system. The slow rates of many transformations and sensitivity of equil. to exact conditions, arising from its varying static and dynamic disorder and water mobility in different phases, meant that characterizing DB7 hydration in terms of simplified hydrate classifications was inappropriate for developing this pharmaceutical.
- 22Bernardes, C. E. S.; da Piedade, M. E. M. Cryst. Growth Des. 2012, 12, 2932– 2941 DOI: 10.1021/cg300134zGoogle Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xnt1Wqu7Y%253D&md5=f9fb28f074e1fa5138b7ec4940ddbce1Crystallization of 4'-Hydroxyacetophenone from Water: Control of Polymorphism via Phase Diagram StudiesBernardes, Carlos E. S.; da Piedade, Manuel E. MinasCrystal Growth & Design (2012), 12 (6), 2932-2941CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)The prepn. of polymorphs and solvates and the characterization of their stability domains have received considerable attention in recent years, due to the importance of these studies for fundamental research and for the prodn. of new materials for task-specific applications. In this work, the selective and reproducible crystn. of different solid forms of 4'-hydroxyacetophenone (HAP) from water was investigated, through the detn. of a temp.-concn. (T-cHAP) phase diagram. This detn. was mainly based on gravimetric soly. measurements, slurry tests, and metastable zone width (MZW) studies with thermometric and turbidity detection. The exptl. conditions for the formation of five different HAP phases by cooling crystn. could be established: the previously characterized anhyd. forms I and II and the hydrate HAP·1.5H2O (H1), and two new hydrates, one of stoichiometry HAP·3H2O (H2) and another (H3) which proved too unstable for a stoichiometry detn. The crystn. precedence of the various phases, their approx. lifetimes, and transformation sequences could also be elucidated. It was finally found that for a specific T-cHAP domain the crystn. of HAP solid phases was mediated by a colloidal dispersion. Preliminary dynamic light scattering expts. indicated that this dispersion consisted of particles with diams. in the range of 100-800 nm.
- 23Pina, M. F.; Pinto, J. F.; Sousa, J. J.; Fabian, L.; Zhao, M.; Craig, D. Q. M. Mol. Pharmaceutics 2012, 9, 3515– 3525 DOI: 10.1021/mp3003573Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVyltbbN&md5=55d9efc8e5d3897053dc23abde4f290dIdentification and Characterization of Stoichiometric and Nonstoichiometric Hydrate Forms of Paroxetine HCl: Reversible Changes in Crystal Dimensions as a Function of Water AbsorptionPina, M. Fatima; Pinto, Joao F.; Sousa, Joao J.; Fabian, Laszlo; Zhao, Min; Craig, Duncan Q. M.Molecular Pharmaceutics (2012), 9 (12), 3515-3525CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Paroxetine hydrochloride (HCl) is an antidepressant drug, reported to exist in the anhyd. form (form II) and as a stable hemihydrate (form I). In this study, we investigate the hydration behavior of paroxetine HCl form II with a view to understanding both the nature of the interaction with water and the interchange between forms II and I as a function of both temp. and water content. In particular, we present new evidence for both the structure and the interconversion process to be more complex than previously recognized. A combination of characterization techniques was used, including thermal (differential scanning calorimetry (DSC) and thermogravimetric anal. (TGA)), spectroscopic (attenuated total reflectance Fourier transform IR spectroscopy (ATR-FTIR)), dynamic vapor sorption (DVS) and X-ray powder diffraction (XRPD) with variable humidity, along with computational mol. modeling of the crystal structures. The total amt. of water present in form II was surprisingly high (3.8% wt./wt., 0.8 mol of water/mol of drug), with conversion to the hemihydrate noted on heating in hermetically sealed DSC pans. XRPD, supported by ATR-FTIR and DVS, indicated changes in the unit cell dimensions as a function of water content, with clear evidence for reversible expansion and contraction as a function of relative humidity (RH). Based on these data, we suggest that paroxetine HCl form II is not an anhydrate but rather a nonstoichiometric hydrate. However, no continuous channels are present and, according to mol. modeling simulation, the water is moderately strongly bonded to the crystal, which is in itself an uncommon feature when referring to nonstoichiometric hydrates. Overall, therefore, we suggest that the anhyd. form of paroxetine HCl is not only a nonstoichiometric hydrate but also one that shows highly unusual characteristics in terms of gradual unit cell expansion and contraction despite the absence of continuous channels. These structural features in turn influence the tendency of this drug to convert to the more stable hemihydrate. The study has implications for the recognition and understanding of the behavior of pharmaceutical nonstoichiometric hydrates.
- 24Stephenson, G. A.; Diseroad, B. A. Int. J. Pharm. 2000, 198, 167– 177 DOI: 10.1016/S0378-5173(00)00331-8Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXitlelurg%253D&md5=c35a958fdeb5bf32e34590b90a180407Structural relationship and desolvation behavior of cromolyn, cefazolin and fenoprofen sodium hydratesStephenson, G. A.; Diseroad, B. A.International Journal of Pharmaceutics (2000), 198 (2), 167-177CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)The hydrated crystal structures of cromolyn, cefazolin, and fenoprofen sodium salts are reported. The former two compds. are non-stoichiometric hydrates, whereas the fenoprofen lattice maintains its stoichiometry over a broad range of relative humidity. The relationship between compn., lattice parameters, and relative humidity is studied using a combination of moisture sorption isotherms and variable humidity X-ray powder diffraction. The dehydration properties of the sodium salts are related to the ion coordination and hydrogen bonding of the water mols. in the structures. Anisotropic lattice contraction is obsd. during dehydration of the cromolyn and cefazolin sodium and is related to the closeness of intermol. contacts in the hydrated structures.
- 25Berzins, A.; Skarbulis, E.; Rekis, T.; Actins, A. Cryst. Growth Des. 2014, 14, 2654– 2664 DOI: 10.1021/cg5003447Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmtlSgtL8%253D&md5=cc3bdefbbc3b5536a7d8d5f9bfec6e72On the Formation of Droperidol Solvates: Characterization of Structure and PropertiesBerzins, Agris; Skarbulis, Edgards; Rekis, Toms; Actins, AndrisCrystal Growth & Design (2014), 14 (5), 2654-2664CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)A solvate screening and characterization of the obtained solvates was performed to rationalize and understand the solvate formation of active pharmaceutical ingredient droperidol (1-{1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydro-4-pyridyl}-1,3-dihydro-2H-benzimidazol-2-one). The solvate screening revealed that droperidol can form 11 different solvates. The anal. of the crystal structures and mol. properties revealed that droperidol solvate formation is mainly driven by the inability of droperidol mols. to pack efficiently. The obtained droperidol solvates were characterized by x-ray diffraction and thermal anal. Droperidol forms 7 nonstoichiometric isostructural solvates, and the crystal structures were detd. for 5 of these solvates. To better understand the structure of these 5 solvates, their solvent sorption-desorption isotherms were recorded, and lattice parameter dependence on the solvent content was detd. This revealed a different behavior of the nonstoichiometic hydrate, which was explained by the simultaneous insertion of 2 H-bonded H2O mols. Isostructural solvates were formed with sufficiently small solvent mols. providing effective intermol. interactions, and solvate formation was rationalized based on already presented solvent classification. The lack of solvent specificity in isostructural solvates was explained by the very effective interactions between droperidol mols. Desolvation of stoichiometric droperidol solvates produced 1 of the 4 droperidol polymorphs, whereas that of nonstoichiometic solvates produced an isostructural desolvate. Crystallog. data are given.
- 26Campeta, A. M.; Chekal, B. P.; Abramov, Y. A.; Meenan, P. A.; Henson, M. J.; Shi, B.; Singer, R. A.; Horspool, K. R. J. Pharm. Sci. 2010, 99, 3874– 3886 DOI: 10.1002/jps.22230Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXptlejsbw%253D&md5=98fc54e1d2ff0cf2e79bfc0807cec36bDevelopment of a targeted polymorph screening approach for a complex polymorphic and highly solvating APICampeta, Anthony M.; Chekal, Brian P.; Abramov, Yuriy A.; Meenan, Paul A.; Henson, Mark J.; Shi, Bing; Singer, Robert A.; Horspool, Keith R.Journal of Pharmaceutical Sciences (2010), 99 (9), 3874-3886CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)Elucidation of the most stable form of an active pharmaceutical ingredient (API) is a crit. step in the development process. Polymorph screening for an API with a complex polymorphic profile can present a significant challenge. The presented case illustrates an extensively polymorphic compd. with an addnl. propensity for forming stable solvates. In all, 5 anhyd. forms and 66 solvated forms have been discovered. After early polymorph screening using common techniques yielded mostly solvates and failed to uncover several key anhyd. forms, it became necessary to devise new approaches based on an advanced understanding of crystal structure and conformational relationships between forms. With the aid of this anal., two screening approaches were devised which targeted high-temp. desolvation as a means to increase conformational populations and enhance overall probability of anhyd. form prodn. Application of these targeted approaches, comprising over 100 expts., produced only the known anhyd. forms, without appearance of any new forms. The development of these screens was a crit. and alternative approach to circumvent solvation issues assocd. with more conventional screening methods. The results provided confidence that the current development form was the most stable polymorph, with a low likelihood for the existence of a more-stable anhyd. form. © 2010 Wiley-Liss, Inc. and the American Pharmacists Assocn. J Pharm Sci 99:3874-3886, 2010.
- 27Zhao, X. S.; Siepmann, J. I.; Xu, W.; Kiang, Y. H.; Sheth, A. R.; Karaborni, S. J. Phys. Chem. B 2009, 113, 5929– 5937 DOI: 10.1021/jp808164tGoogle ScholarThere is no corresponding record for this reference.
- 28Morissette, S. L.; Almarsson, O.; Peterson, M. L.; Remenar, J. F.; Read, M. J.; Lemmo, A. V.; Ellis, S.; Cima, M. J.; Gardner, C. R. Adv. Drug Delivery Rev. 2004, 56, 275– 300 DOI: 10.1016/j.addr.2003.10.020Google ScholarThere is no corresponding record for this reference.
- 29Aaltonen, J.; Alleso, M.; Mirza, S.; Koradia, V.; Gordon, K. C.; Rantanen, J. Eur. J. Pharm. Biopharm. 2009, 71, 23– 37 DOI: 10.1016/j.ejpb.2008.07.014Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsV2lurbF&md5=f7296a912891c6e96d6cb42a351a6478Solid form screening - A reviewAaltonen, Jaakko; Alleso, Morten; Mirza, Sabiruddin; Koradia, Vishal; Gordon, Keith C.; Rantanen, JukkaEuropean Journal of Pharmaceutics and Biopharmaceutics (2009), 71 (1), 23-37CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)A review. Solid form screening, the activity of generating and analyzing different solid forms of an active pharmaceutical ingredient (API), has become an essential part of drug development. The multi-step screening process needs to be designed, performed and evaluated carefully, since the decisions made based on the screening may have consequences on the whole lifecycle of a pharmaceutical product. The selection of the form for development is made after solid form screening. The selection criteria include not only pharmaceutically relevant properties, such as therapeutic efficacy and processing characteristics, but also intellectual property (IP) issues. In this paper, basic principles of solid form screening are reviewed, including the methods used in exptl. screening (generation, characterization and anal. of solid forms, data mining tools, and high-throughput screening technologies) as well as basics of computational methods. Differences between solid form screening strategies of branded and generic pharmaceutical manufacturers are also discussed.
- 30Allesoe, M.; Tian, F.; Cornett, C.; Rantanen, J. J. Pharm. Sci. 2010, 99, 3711– 3718 DOI: 10.1002/jps.21957Google ScholarThere is no corresponding record for this reference.
- 31Rasanen, E.; Rantanen, J.; Jorgensen, A.; Karjalainen, M.; Paakkari, T.; Yliruusi, J. J. Pharm. Sci. 2001, 90, 389– 396 DOI: 10.1002/1520-6017(200103)90:3<389::AID-JPS13>3.0.CO;2-9Google ScholarThere is no corresponding record for this reference.
- 32Wikstroem, H.; Kakidas, C.; Taylor, L. S. J. Pharm. Biomed. Anal. 2009, 49, 247– 252 DOI: 10.1016/j.jpba.2008.11.008Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhs1alsr4%253D&md5=719cac492bf441cc02789b9ab7975f7fDetermination of hydrate transition temperature using transformation kinetics obtained by Raman spectroscopyWikstroem, Hakan; Kakidas, Christopher; Taylor, Lynne S.Journal of Pharmaceutical and Biomedical Analysis (2009), 49 (2), 247-252CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)The thermodn. transition temp. is a key parameter to ascertain when assessing the properties of a cryst. hydrate. The transition temp. is sometimes difficult to det. exptl. due to rapid transformation between the two crystal forms in soln. In this study, a new approach for detg. the transition temp. is presented, utilizing the temp. dependence of the transformation kinetics in aq. slurries, as detd. using in-line Raman spectroscopy. The transition temps. of several hydrate forming compds., namely theophylline, carbamazepine and caffeine, are presented. In general, good correlations with literature values were found. This method was found to be a simple, fast and reliable approach for the detn. of crystal hydrate transition temps. in aq. environments.
- 33Morris, K. R.; Griesser, U. J.; Eckhardt, C. J.; Stowell, J. G. Adv. Drug Delivery Rev. 2001, 48, 91– 114 DOI: 10.1016/S0169-409X(01)00100-4Google ScholarThere is no corresponding record for this reference.
- 34Tantry, J. S.; Tank, J.; Suryanarayanan, R. J. Pharm. Sci. 2007, 96, 1434– 1444 DOI: 10.1002/jps.20746Google ScholarThere is no corresponding record for this reference.
- 35Debnath, S.; Suryanarayanan, R. AAPS PharmSciTech 2004, 5, 39 DOI: 10.1208/pt050108Google ScholarThere is no corresponding record for this reference.
- 36Chakravarty, P.; Suryanarayanan, R.; Govindarajan, R. J. Pharm. Sci. 2012, 101, 1410– 1422 DOI: 10.1002/jps.23020Google ScholarThere is no corresponding record for this reference.
- 37Griesser, U. J. In Polymorphism: In the Pharmaceutical Industry; Hilfiker, R., Ed.; Wiley-VCH: Weinheim, Germany, 2006; pp 211– 233.Google ScholarThere is no corresponding record for this reference.
- 38Te, R. L.; Griesser, U. J.; Morris, K. R.; Byrn, S. R.; Stowell, J. G. Cryst. Growth Des. 2003, 3, 997– 1004 DOI: 10.1021/cg0340749Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmt1Kkurw%253D&md5=3bbc0c300056ae33115a5e58af3d1811X-ray Diffraction and Solid-State NMR Investigation of the Single-Crystal to Single-Crystal Dehydration of Thiamine Hydrochloride MonohydrateTe, Ruth L.; Griesser, Ulrich J.; Morris, Kenneth R.; Byrn, Stephen R.; Stowell, Joseph G.Crystal Growth & Design (2003), 3 (6), 997-1004CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)The dehydration of a thiamine hydrochloride (vitamin B1) hydrate, commonly referred to as the monohydrate, was investigated by solid-state NMR (SSNMR) and X-ray diffraction (XRD) techniques. The hydrate can be classified as a nonstoichiometric solvate since the water content depends on the water vapor pressure of the surrounding atm. and essentially maintains the three-dimensional mol. arrangement upon dehydration. Thus, we were able to det. the crystal structures of both the hydrate and the isomorphic desolvate with one single crystal. The loss of water leads to a shrinkage of the unit cell vol. of about 5% and to a slight increase in the free vol. This is also accompanied by an increase in mol. motion as is demonstrated by SSNMR 1H and 13C T1 measurements. The largest change in T1 was obsd. for the carbons of the hydroxyethyl functional group that is hydrogen bonded to the water mols. in the hydrate. This investigation confirms that an increase in free vol. results in an increase in mol. mobility and demonstrates the impact of mol. interactions on the mobility of specific mol. entities.
- 39Otsuka, M.; Kaneniwa, N. Yakugaku Zasshi 1982, 102, 359– 364Google ScholarThere is no corresponding record for this reference.
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- 42Stephenson, G. A.; Groleau, E. G.; Kleemann, R. L.; Xu, W.; Rigsbee, D. R. J. Pharm. Sci. 1998, 87, 536– 542 DOI: 10.1021/js970449zGoogle ScholarThere is no corresponding record for this reference.
- 43Mimura, H.; Kitamura, S.; Kitagawa, T.; Kohda, S. Colloids Surf., B 2002, 26, 397– 406 DOI: 10.1016/S0927-7765(02)00026-7Google ScholarThere is no corresponding record for this reference.
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- 47Boiadjiev, S. E.; Person, R. V.; Puzicha, G.; Knobler, C.; Maverick, E.; Trueblood, K. N.; Lightner, D. A. J. Am. Chem. Soc. 1992, 114, 10123– 10133 DOI: 10.1021/ja00052a006Google ScholarThere is no corresponding record for this reference.
- 48Dijksma, F. J. J.; Gould, R. O.; Parsons, S.; Taylor, P.; Walkinshaw, M. D. Chem. Commun. 1998, 745– 746 DOI: 10.1039/a800219cGoogle ScholarThere is no corresponding record for this reference.
- 49Agrawal, S. S.; Saraswati, S.; Mathur, R.; Pandey, M. Life Sci. 2011, 89, 147– 158 DOI: 10.1016/j.lfs.2011.05.020Google ScholarThere is no corresponding record for this reference.
- 50Chen, H. b.; Ma, F. s.; Fang, J. q.; Fang, F. Zhongchengyao 2015, 37, 16– 21Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1alsrnF&md5=6660dc562b1aa4e387c43ab289e01de8Cytotoxicity of components from seeds of Strychnos nuxvomica to human HaCaT keratinocytesChen, Hai-bo; Ma, Feng-sen; Fang, Jian-qiao; Fang, FangZhongchengyao (2015), 37 (1), 16-21CODEN: ZHONBS; ISSN:1001-1528. (Zhongchengyao Zazhi Bianjibu)The purpose of the research is to study the cytotoxicity of alkaloids from Strychni Semen and its different components on HaCaT cell, an immortalized human epidermal cell line. In vitro cultured HaCaT cells co-cultured with same concns. of brucine, strychnine, and the mixt. of brucine and strychnine, total alkaloids from Strychni Semen for 24 h, the no. of viable cells was obsd. by using the MTT method. The cell apoptotic rate was detected and calcd. by flow cytometry. Cytotoxicity on HaCaT cell was compared among different components of alkaloids from Strychni Semen. The proliferation rates and the apoptotic rate of strychnine on HaCaT were greater than brucine at the same concn., the mixt. of brucine and strychnine on HaCaT were greater than total alkaloids from Strychni Semen similarly in those two rates. The components of alkaloids from Strychni Semen have obvious cytotoxicity to HaCaT cell in a dose-dependent relationship, meanwhile, cytotoxicity of brucine is lower than that of strychnine.
- 51Deng, X. K.; Yin, W.; Li, W. D.; Yin, F. Z.; Lu, X. Y.; Zhang, X. C.; Hua, Z. C.; Cai, B. C. J. Ethnopharmacol. 2006, 106, 179– 186 DOI: 10.1016/j.jep.2005.12.021Google ScholarThere is no corresponding record for this reference.
- 52Yin, W.; Deng, X. K.; Yin, F. Z.; Zhang, X. C.; Cai, B. C. Food Chem. Toxicol. 2007, 45, 1700– 1708 DOI: 10.1016/j.fct.2007.03.004Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXot12ksrs%253D&md5=c6d067d8e0b29ecdf7767cd916e8f0e7The cytotoxicity induced by brucine from the seed of Strychnos nux-vomica proceeds via apoptosis and is mediated by cyclooxygenase 2 and caspase 3 in SMMC 7221 cellsYin, Wu; Deng, Xu-Kun; Yin, Fang-Zhou; Zhang, Xiao-Chun; Cai, Bao-ChangFood and Chemical Toxicology (2007), 45 (9), 1700-1708CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)To study the cytotoxicity of four alkaloids: brucine, strychnine, brucine N-oxide and isostrychnine from nux vomica on SMMC 7721 cells and their possible mechanisms, MET assay was used to examine the growth inhibitory effects of these alkaloids. Brucine revealed the strongest growth inhibitory effect on SMMC-7721 cells. Furthermore, as directly obsd. under an inverted microscope, fluorescent microscope and transmission electronic microscope, brucine caused SMMC-7721 cell shrinkage, membrane blobbing, formation of apoptotic body as well as nucleus condensation, all of which are typical characteristics of apoptotic programmed cell death. In addn., brucine dose-dependently caused SMMC-7721 cells apoptosis via formation of subdipolid DNA and phosphatidylserine externalization, as evidenced by flow cytometry anal. The brucine-induced apoptosis was partially attributed to the activation of caspase 3 as well as cyclooxygenase 2 inhibition, since neither caspase 3 specific inhibitor, z-DEVD-fmk nor was exogenous addn. of prostaglandin E2 able to completely abrogate the brucine-induced SMMC 7721 cell apoptosis. In sum, this paper indicate that the major alkaloids present in the seed of Strychnos nux-vomica are effective against SMMC-7721 cells proliferation, among which brucine proceeds SMMC-7721 cells death via apoptosis, probably through the participation of caspase 3 and cyclooxygenase 2.
- 53Rao, P. S.; Ramanadham, M.; Prasad, M. N. V. Food Chem. Toxicol. 2009, 47, 283– 288 DOI: 10.1016/j.fct.2008.10.027Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotl2ksA%253D%253D&md5=267bc1bffd8e25651e16e1053b98ffd3Anti-proliferative and cytotoxic effects of Strychnos nux-vomica root extract on human multiple myeloma cell line - RPMI 8226Rao, Pasupuleti Sreenivasa; Ramanadham, Madduri; Prasad, Majeti Narasimha VaraFood and Chemical Toxicology (2009), 47 (2), 283-288CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)Multiple myeloma (MM) is an incurable hematol. malignancy with high incidence in the elderly. The currently used chemotherapeutic drugs show severe side effects, dose-limiting toxicity and development of resistance. In search of novel plant derived anti-cancer agents, Strychnos nux-vomica L. (SN) root ext. was screened using the human MM-cell line, RPMI 8226. SN-ext. exhibited anti-proliferative activity in a dose and time dependent manner. The morphol. assessment of SN-ext. treated cells showed significant features assocd. with apoptosis. Cell cycle anal. using flow cytometry of cells stained with propidium iodide revealed accumulation of cells at sub-G0/G1 phase. In addn., disruption of mitochondrial membrane potential and subsequent leakage of mitochondrial cytochrome c was obsd. in SN-ext. treated myeloma cells. The anti-proliferative and cytotoxic activity could be due to the alkaloids strychnine and brucine, which have been identified by LC-mass spectral anal. of the SN-ext. in comparison to the ref. stds. analyzed under identical conditions.
- 54Chen, J.; Wang, X.; Qu, Y. g.; Chen, Z. p.; Cai, H.; Liu, X.; Xu, F.; Lu, T. l.; Cai, B. C. J. Ethnopharmacol. 2012, 139, 181– 188 DOI: 10.1016/j.jep.2011.10.038Google ScholarThere is no corresponding record for this reference.
- 55Groth, P. Chemische Krystallographie. Teil 5. Aromatische Kohlenstoffverbindungen mit mehreren Benzolringen heterocyclische Verbindungen; W. Engelmann: Leipzig, Germany, 1919; Vol. 5.Google ScholarThere is no corresponding record for this reference.
- 56Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C. Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 2016, 72, 171– 179 DOI: 10.1107/S2052520616003954Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xls1Kntro%253D&md5=f9c65ab86fc9db429588c95b0da3f9b2The Cambridge Structural DatabaseGroom, Colin R.; Bruno, Ian J.; Lightfoot, Matthew P.; Ward, Suzanna C.Acta Crystallographica, Section B: Structural Science, Crystal Engineering and Materials (2016), 72 (2), 171-179CODEN: ACSBDA; ISSN:2052-5206. (International Union of Crystallography)The Cambridge Structural Database (CSD) contains a complete record of all published org. and metal-org. small-mol. crystal structures. The database has been in operation for over 50 years and continues to be the primary means of sharing structural chem. data and knowledge across disciplines. As well as structures that are made public to support scientific articles, it includes many structures published directly as CSD Communications. All structures are processed both computationally and by expert structural chem. editors prior to entering the database. A key component of this processing is the reliable assocn. of the chem. identity of the structure studied with the exptl. data. This important step helps ensure that data is widely discoverable and readily reusable. Content is further enriched through selective inclusion of addnl. exptl. data. Entries are available to anyone through free CSD community web services. Linking services developed and maintained by the CCDC, combined with the use of std. identifiers, facilitate discovery from other resources. Data can also be accessed through CCDC and third party software applications and through an application programming interface.
- 57Bialonska, A.; Ciunik, Z. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, 60, o853– o855 DOI: 10.1107/S0108270104024874Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVeku7zP&md5=2db2ebdbf91fe44236c50732bf33e10aBrucine and two solvatesBialonska, Agata; Ciunik, ZbigniewActa Crystallographica, Section C: Crystal Structure Communications (2004), C60 (12), o853-o855CODEN: ACSCEE; ISSN:0108-2701. (Blackwell Publishing Ltd.)The crystal structures of brucine (2,3-dimethoxystrychnidin-10-one), C23H26N2O4, brucine acetone solvate, C23H26N2O4·C3H6O, and brucine iso-PrOH solvate dihydrate, C23H26N2O4·C3H7O·2H2O, were detd. Crystallog. data are given. Crystals of brucine and its iso-PrOH solvate dihydrate exhibit similar monolayer sheet packing, whereas crystals of the acetone solvate adopt a different mode of packing, as brucine pillars. The solvent appears to control the brucine self-assembly from common donor-acceptor properties of the surfaces.
- 58Bialonska, A.; Ciunik, Z.; Ilczyszyn, M. M.; Siczek, M. Cryst. Growth Des. 2014, 14, 6537– 6541 DOI: 10.1021/cg501437gGoogle Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFWjs7%252FK&md5=d04e2f38b80855fd451c3909437f5087Discrete Cuboidal 15- and 16-Membered Water Clusters in Brucine 3.86-Hydrate, Water Release and Its ConsequencesBialonska, Agata; Ciunik, Zbigniew; Ilczyszyn, Maria M.; Siczek, MiloszCrystal Growth & Design (2014), 14 (12), 6537-6541CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)Up to now, three brucine hydrates are known, brucine di-, tetra-, and 5.25-hydrate. All of them were obtained from solns. contg. the additive diethanolamine, adenosine, and urea, resp. Studying the role of the additives on crystn. of the brucine hydrates, the authors obtained a new, kinetically favored brucine 3.86-hydrate. In crystals of brucine 3.86-hydrate, large 15- and 16-membered water clusters of cuboidal topol. are encapsulated in cages formed between honeycomb-like brucine layers. Dehydration of the brucine hydrate leads to formation of the known anhyd. brucine, giving insight into a mechanism of the dehydration process, in which a shift of brucine ribbons in the honeycomb-like layers leads to an opening of channels and water release. A collapse of brucine layers after the water release results in formation of the common anhyd. brucine. The anhyd. brucine undergoes a phase transition at 249 K in the cooling mode and at 277 K in the heating mode. The phase transition is attributable to a huge shift of brucine corrugated layers in relation to each other. The phase transition for anhyd. brucine obtained by dehydration is accompanied by thermal effects one order larger than anhyd. brucine, obtained by crystn. from acetone soln.
- 59Smith, G.; Wermuth, U. D.; White, J. M. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2007, 63, o489– o492 DOI: 10.1107/S0108270107032295Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosVKnsrc%253D&md5=a552f10c893d6f8930ed2964d4d362c4Pseudopolymorphism in brucine: brucine-water (1/2), the third crystal hydrate of brucineSmith, Graham; Wermuth, Urs D.; White, Jonathan M.Acta Crystallographica, Section C: Crystal Structure Communications (2007), 63 (8), o489-o492CODEN: ACSCEE; ISSN:0108-2701. (International Union of Crystallography)The structure of a 3rd pseudopolymorphic hydrate of brucine, brucine-H2O (1/2) [systematic name: 2,3-dimethoxystrychnidin-10-one-H2O (1/2)], C23H26N2O4·2H2O, was detd. at 130 K. Crystallog. data are given. The asym. unit comprises two independent brucine mols. and four H2O mols. of solvation. The four H2O mols. form uncommon cyclic H-bonded homomol. R44(8) tetramer rings, which then form primary H-bonded chain substructures extending down the 21 screw axis in the unit cell. The two brucine mols. are linked peripherally to these substructures by either single O-H···Nbrucine or asym. three-center O-H···Obrucine H bonds.
- 60Smith, G.; Wermuth, U. D.; Healy, P. C.; White, J. M. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2006, 62, o203– o207 DOI: 10.1107/S0108270106005944Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjtFOqsb0%253D&md5=dc824374ec8287ab24080150b3d53ed7Two pseudopolymorphic hydrates of brucine: brucine-water (1/4) and brucine-water (1/5.25) at 130 KSmith, Graham; Wermuth, Urs D.; Healy, Peter C.; White, Jonathan M.Acta Crystallographica, Section C: Crystal Structure Communications (2006), C62 (4), o203-o207CODEN: ACSCEE; ISSN:0108-2701. (Blackwell Publishing Ltd.)The structures of two pseudopolymorphic hydrates of brucine, C23H26N2O4·4H2O, (I), and C23H26N2O4·5.25H2O, (II), were detd. at 130 K. In both (I) and (II) (which has two independent brucine mols. together with 10.5 H2O mols. of solvation in the asym. unit), the brucine mols. form head-to-tail sheet substructures, which assoc. with the H2O mols. in the interstitial cavities through H-bonding assocns. and, together with water-H2O assocns., give three-dimensional framework structures.
- 61Watabe, T.; Kobayashi, K.; Hisaki, I.; Tohnai, N.; Miyata, M. Bull. Chem. Soc. Jpn. 2007, 80, 464– 475 DOI: 10.1246/bcsj.80.464Google ScholarThere is no corresponding record for this reference.
- 62Glover, S. S. B.; Gould, R. O.; Walkinshaw, M. D. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1985, 41, 990– 994 DOI: 10.1107/S0108270185006308Google ScholarThere is no corresponding record for this reference.
- 63Bialonska, A.; Ciunik, Z. CrystEngComm 2013, 15, 5681– 5687 DOI: 10.1039/c3ce40512eGoogle ScholarThere is no corresponding record for this reference.
- 64Goelles, F. Monatsh. Chem. 1961, 92, 981– 991 DOI: 10.1007/BF00924763Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF38XlslOjsQ%253D%253D&md5=67008f5c8c1028b8f0306fcd6334fff0The examination and calculation of thermodynamic data from experimental measurements. I. The numerical integration of the vapor-pressure curves of the system methanol-waterGoelles, F.Monatshefte fuer Chemie (1961), 92 (), 981-91CODEN: MOCMB7; ISSN:0026-9247.The vapor-pressure curves of the system (Butler, et al., CA 27, 4464) were checked for thermodynamic consistency by the independent methods of Runge (Collatz, Numerische Behandlung yon Differentialgleichungen, 1951, Springer, Berlin) and Musil and Breitenhuber (CA 48, 4274h), and the activity coeffs. were recalcd. The calcd. values of the vapor-phase compn. lie between the exptl. values of Butler, et al. (loc. tit.) and those of Froemke, et al. (CA 28, 3918). The calcd. activity coeffs. of water (f1) and MeOH (f2) are given at the following mole fractions of MeOH: 0.1, 1.580, 0.994; 0.2, 1.461, 1.036; 0.3, 1.303, 1.068; 0.4, 1.175, 1.090; 0.5, 1.118, 1.139; 0.6, 1.068, 1.160; 0.7, 1.050, 1.192; 0.8, 1.025, 1.270; 0.9, 1.010, 1.479. The max. discrepancy between f1 exptl. and f1 calcd. is 10%, when x = 0.1.
- 65Zhu, H.; Yuen, C.; Grant, D. J. W. Int. J. Pharm. 1996, 135, 151– 160 DOI: 10.1016/0378-5173(95)04466-3Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjsVOqsr0%253D&md5=e70cda80586c4da5fc96df6c0417fe01Influence of water activity in organic solvent + water mixtures on the nature of the crystallizing drug phase. 1. TheophyllineZhu, Haijian; Yuen, Ceaminia; Grant, David J. W.International Journal of Pharmaceutics (1996), 135 (1,2), 151-160CODEN: IJPHDE; ISSN:0378-5173. (Elsevier)The hydration state of a hydrate depends on the water activity, aw, in the crystn. medium. Selection of an appropriate ratio of water to cosolvent in the crystn. medium of a hydrate is crit. and is often semi-empirical. This study attempts to elucidate this selection process by studying the conditions of phys. stability of the solid phases of theophylline, which comprise an anhydrate and a monohydrate. A mixt. of the anhydrate and the monohydrate may sometimes be obtained, if the system is not in equil. The excess solid phase was characterized by powder X-ray diffractometry and the water content was measured by Karl-Fischer titrimetry. In contact with methanol + water or 2-propanol (iso-Pr alc., IPA) + water mixts., at aw<0.25, the anhydrate was the only solid phase at equil., no matter which solid form was initially added. At aw>0.25 in either solvent mixt., the monohydrate was obtained as the most stable form at equil. These results suggest (a) that water activity is the major factor detg. the nature of the solid phase of theophylline which crystallizes from methanol + water or IPA + water mixts. and (b) that the system, theophylline anhydrate .dblharw. theophylline monohydrate, is in equil. at aw = 0.25 and at 25°C. The solubilities of the two solid forms in each of the mixed solvent systems were also measured and are discussed. The concepts presented, tested and discussed may, in principle, be applied to any pharmaceutical system consisting of an anhydrate and a hydrate, or a lower hydrate and a higher hydrate.
- 66Aspen Properties, version 8.4; Aspen Technology, Inc.: Bedford, MA, 2015.Google ScholarThere is no corresponding record for this reference.
- 67Markvardsen, A. J.; David, W. I. F.; Johnson, J. C.; Shankland, K. Acta Crystallogr., Sect. A: Found. Crystallogr. 2001, 57, 47– 54 DOI: 10.1107/S0108767300012174Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXovF2nsLs%253D&md5=8a0c6a09ce2d11ab9af12e5a8369a8a5A probabilistic approach to space-group determination from powder diffraction dataMarkvardsen, A. J.; David, W. I. F.; Johnston, J. C.; Shankland, K.Acta Crystallographica, Section A: Foundations of Crystallography (2001), A57 (1), 47-54CODEN: ACACEQ; ISSN:0108-7673. (Munksgaard International Publishers Ltd.)An algorithm for the detn. of the space-group symmetry of a crystal from powder diffraction data, based upon probability theory, is described. Specifically, the relative probabilities of different extinction symbols are assessed within a particular crystal system. In general, only a small no. of extinction symbols are relatively highly probable and a single extinction symbol is often significantly more probable than any other. Several examples are presented to illustrate this approach.
- 68David, W. I. F.; Shankland, K.; van de Streek, J.; Pidcock, E.; Motherwell, W. D. S.; Cole, J. C. J. Appl. Crystallogr. 2006, 39, 910– 915 DOI: 10.1107/S0021889806042117Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1KrurjK&md5=ff86f9794641c07a843f9b28a1761865DASH. A program for crystal structure determination from powder diffraction dataDavid, William I. F.; Shankland, Kenneth; van de Streek, Jacco; Pidcock, Elna; Motherwell, W. D. Samuel; Cole, Jason C.Journal of Applied Crystallography (2006), 39 (6), 910-915CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)DASH is a user-friendly graphical-user-interface-driven computer program for solving crystal structures from X-ray powder diffraction data, optimized for mol. structures. Algorithms for multiple peak fitting, unit-cell indexing and space-group detn. are included as part of the program. Mol. models can be read in a no. of formats and automatically converted to Z-matrixes in which flexible torsion angles are automatically identified. Simulated annealing is used to search for the global min. in the space that describes the agreement between obsd. and calcd. structure factors. The simulated annealing process is very fast, which in part is due to the use of correlated integrated intensities rather than the full powder pattern. Automatic minimization of the structures obtained by simulated annealing and automatic overlay of solns. assist in assessing the reproducibility of the best soln., and therefore in detg. the likelihood that the global min. was obtained.
- 69Pawley, G. S. J. Appl. Crystallogr. 1981, 14, 357– 361 DOI: 10.1107/S0021889881009618Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38XhtlylsA%253D%253D&md5=56e059d8b778190e1f9e9076b68abf96Unit-cell refinement from powder diffraction scansPawley, G. S.Journal of Applied Crystallography (1981), 14 (6), 357-61CODEN: JACGAR; ISSN:0021-8898.A procedure for the refinement of the crystal unit cell from a powder diffraction scan is presented. Knowledge of the crystal structure is not required, and at the end of the refinement a list of indexed intensities is produced. This list may well be usable as the starting point for the application of direct methods. The problems of least-square ill-conditioning due to overlapping reflections are overcome by constraints. An example, using decafluorocyclohexene shows the quality of fit obtained in a case which may even be a false min. The method should become more relevant as powd. scans of improved resoln. become available, through the use of pulsed neutron sources.
- 70Rietveld, H. M. J. Appl. Crystallogr. 1969, 2, 65– 71 DOI: 10.1107/S0021889869006558Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1MXksVeisbk%253D&md5=3e3acdf00920ecd78a9bc042511e7fc4Profile refinement method for nuclear and magnetic structuresRietveld, H. M.Journal of Applied Crystallography (1969), 2 (Pt. 2), 65-71CODEN: JACGAR; ISSN:0021-8898.A structural refinement method for neutron diffraction is presented which makes direct use of the profile intensities obtained from the powder diagram. It is applicable to nuclear structures and to magnetic structures which can be described on the nuclear unit cell or a multiple thereof. Equations for the measured profiles to be used in the least sqs. treatment are cor. for asymmetry and preferred orientation; the angular dependence of the half widths of the peaks is given by the formula of Caglioti, et al. (1958). The magnetic contribution to the profile equation is expressed by calcg. only one av. cross section for each set of equiv. reflections. It is possible to introduce constraint functions, linear or quadratic, between parameters used in the least sqs. treatment. Results of the use of this method are given for a series of compds. In all instances it has proved superior to any other method involving integrated neutron powder intensities, single or overlapping.
- 71Coelho, A. A.TOPAS Academic V5; Coelho Software: Brisbane, Australia, 2012.Google ScholarThere is no corresponding record for this reference.
- 72Ahlqvist, M. U. A.; Taylor, L. S. J. Pharm. Sci. 2002, 91, 690– 698 DOI: 10.1002/jps.10068Google ScholarThere is no corresponding record for this reference.
- 73Braun, D. E.; Tocher, D. A.; Price, S. L.; Griesser, U. J. J. Phys. Chem. B 2012, 116, 3961– 3972 DOI: 10.1021/jp211948qGoogle ScholarThere is no corresponding record for this reference.
- 74Zencirci, N.; Gstrein, E.; Langes, C.; Griesser, U. J. Thermochim. Acta 2009, 485, 33– 42 DOI: 10.1016/j.tca.2008.12.001Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhvF2jtL8%253D&md5=f6f6990dc4414b2b02bc753adbe5161cTemperature- and moisture-dependent phase changes in crystal forms of barbituric acidZencirci, Neslihan; Gstrein, Elisabeth; Langes, Christoph; Griesser, Ulrich J.Thermochimica Acta (2009), 485 (1-2), 33-42CODEN: THACAS; ISSN:0040-6031. (Elsevier B.V.)The dihydrate of barbituric acid (BAc) and its dehydration product, form II were investigated by moisture sorption anal., hot-stage microscopy, differential scanning calorimetry, thermogravimetry, soln. calorimetry, IR- and Raman spectroscopy, as well as powder x-ray diffraction. The dihydrate desolvates already at and below 50% relative humidity (RH) at 25° whereas form II is stable ≤80% RH, where it transforms back to the dihydrate. The thermal dehydration of barbituric acid dihydrate (BAc-H2) is a single step, nucleation controlled process. The peritectic reaction of the hydrate was measured at 77° and a transformation enthalpy of ΔtrsHH2-II = 17.3 kJ mol-1 was calcd. for the interconversion between the hydrate and form II. An almost identical value of 17.0 kJ mol-1 was obtained from soln. calorimetry in water as solvent (ΔsolHH2 = 41.5, ΔsolHII = 24.5 kJ mol-1). Addnl. a high-temp. form (HT-form) of BAc, which is enantiotropically related to form II and unstable at ambient conditions was characterized. Furthermore, we obsd. that grinding of BAc with KBr induces a tautomeric change. Therefore, IR-spectra recorded with KBr-disks usually display a mixt. of tautomers, whereas the IR-spectra of the pure trioxo-form of BAc are obtained if alternative prepn. techniques are used.
- 75Braun, D. E.; Orlova, M.; Griesser, U. J. Cryst. Growth Des. 2014, 14, 4895– 4900 DOI: 10.1021/cg501159cGoogle Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFSqtbvJ&md5=33ca21837567f57b653af0ee554b5ac6Creatine: Polymorphs Predicted and FoundBraun, Doris E.; Orlova, Maria; Griesser, Ulrich J.Crystal Growth & Design (2014), 14 (10), 4895-4900CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)Hydrate and anhydrate crystal structure prediction (CSP) of creatine (CTN), a heavily used, poorly water-sol., zwitterionic compd., has enabled the finding and characterization of its anhydrate polymorphs, including the thermodn. room temp. form. Crystal structures of the novel forms were detd. by combining lab. powder X-ray diffraction data and ab initio generated structures. The computational method not only revealed all exptl. forms but also predicted the correct stability order, which was exptl. confirmed by measurements of the heat of hydration.
- 76Braun, D. E.; Oberacher, H.; Arnhard, K.; Orlova, M.; Griesser, U. J. CrystEngComm 2016, 18, 4053– 4067 DOI: 10.1039/C5CE01758KGoogle ScholarThere is no corresponding record for this reference.
- 77Riddick, J. A.; Bunger, W. B. Organic Solvents: Physical Properties and Methods of Purification, 4th ed.; Techniques of Chemistry; Wiley-Interscience: New York, 1986; Vol. 2.Google ScholarThere is no corresponding record for this reference.
- 78
In DSC experiments of hydrates, performed with hermetically sealed pans, any water that is released from the hydrate will be kept in the system. An equilibrium water vapor pressure will build up in the small volume above the sample. Thus, the composition of the condensed phase will remain relatively constant.
There is no corresponding record for this reference. - 79Van der Spoel, D.; Van Maaren, P. J.; Larsson, P.; Timneanu, N. J. Phys. Chem. B 2006, 110, 4393– 4398 DOI: 10.1021/jp0572535Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFegtr4%253D&md5=520e1796834b151a6987d6405a38799cThermodynamics of Hydrogen Bonding in Hydrophilic and Hydrophobic MediaVan der Spoel, David; Van Maaren, Paul J.; Larsson, Per; Timneanu, NicusorJournal of Physical Chemistry B (2006), 110 (9), 4393-4398CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)The thermodn. of hydrogen bond breaking and formation was studied in aq. solns. of alc. (methanol, ethanol, 1-propanol) mols. An extensive series of over 400 mol. dynamics simulations with an aggregate length of over 900 ns was analyzed using an anal. technique in which hydrogen bond (HB) breaking is interpreted as an Eyring process, for which the Gibbs energy of activation ΔG⧧ can be detd. from the HB lifetime. By performing simulations at different temps., we were able to det. the enthalpy of activation ΔH⧧ and the entropy of activation TΔS⧧ for this process from the Van't Hoff relation. The equil. thermodn. was detd. sep., based on the no. of donor hydrogens that are involved in hydrogen bonds. Results (ΔH) are compared with exptl. data from Raman spectroscopy and found to be in good agreement for pure water and methanol. The ΔG as well as the ΔG⧧ are smooth functions of the compn. of the mixts. The main result of the calcns. is that ΔG is essentially independent of the environment (around 5 kJ/mol), suggesting that buried hydrogen bonds (e.g., in proteins) do not contribute significantly to protein stability. Enthalpically, HB formation is a downhill process in all substances; however, for the alcs. there is an entropic barrier of 6-7 kJ/mol, at 298.15 K, which cannot be detected in pure water.
- 80Markovitch, O.; Agmon, N. J. Phys. Chem. A 2007, 111, 2253– 2256 DOI: 10.1021/jp068960gGoogle ScholarThere is no corresponding record for this reference.
- 81Wendler, K.; Thar, J.; Zahn, S.; Kirchner, B. J. Phys. Chem. A 2010, 114, 9529– 9536 DOI: 10.1021/jp103470eGoogle Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVahsbjI&md5=6435e81c9715149cdaf7dd200f4cad11Estimating the Hydrogen Bond EnergyWendler, Katharina; Thar, Jens; Zahn, Stefan; Kirchner, BarbaraJournal of Physical Chemistry A (2010), 114 (35), 9529-9536CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)First, different approaches to detect hydrogen bonds and to evaluate their energies are introduced newly or are extended. Supermol. interaction energies of 256 dimers, each contg. one single hydrogen bond, were correlated to various descriptors by a fit function depending both on the donor and acceptor atoms of the hydrogen bond. On the one hand, descriptors were orbital-based parameters as the two-center or three-center shared electron no., products of ionization potentials and shared electron nos., and the natural bond orbital interaction energy. On the other hand, integral descriptors examd. were the acceptor-proton distance, the hydrogen bond angle, and the IR frequency shift of the donor-proton stretching vibration. Whereas an interaction energy dependence on 1/r3.8 was established, no correlation was found for the angle. Second, the fit functions are applied to hydrogen bonds in polypeptides, amino acid dimers, and water cluster, thus their reliability is demonstrated. Employing the fit functions to assign intramol. hydrogen bond energies in polypeptides, several side chain CH···O and CH···N hydrogen bonds were detected on the fly. Also, the fit functions describe rather well intermol. hydrogen bonds in amino acid dimers and the cooperativity of hydrogen bond energies in water clusters.
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Abstract
Figure 1
Figure 1. Molecular diagram of brucine (2,3-dimethoxystrychnidin-10-one).
Figure 2
Figure 2. (a) Gravimetric moisture sorption and desorption curves of brucine HyA at 25 °C. Note that measurement points from sorption and desorption cycles coincide. (b) Fractional occupancies of water molecules derived from Rietveld refinements of the PXRD patterns recorded at different RH values. (c) Void space analysis of HyA (CIKDOQ (59)), excluding the water molecules, showing the water channels along the crystallographic b axis. Water space was calculated using the Hydrate Analyzer tool in Mercury and a probe radius and approximately a grid spacing of 1.2 and 0.15 Å, respectively.
Figure 3
Figure 3. (a) Moisture-dependent PXRD measurements of HyA. Numbers on the y axis indicate the moisture in % at which the powder pattern was recorded. (b) Packing diagrams of HyA highlighting the water oxygen positions (W1–W4) at different HyA hydration states. Fractions correspond to water occupancies and were derived from Rietveld refinements (Table S5 of the Supporting Information). For clarity, water hydrogen atoms are omitted in (b).
Figure 4
Figure 4. (a) Gravimetric moisture sorption and desorption curves of HyB/amorphous brucine at 25 °C. (b) Moisture-dependent PXRD measurements starting from HyB. Numbers on the y axis indicate the moisture in % at which the powder pattern was recorded. Dotted lines in (b) indicate the presence of other not further characterized phase(s). B and C denote characteristic low-angle reflections of HyB and HyC, respectively.
Figure 5
Figure 5. (a) Gravimetric moisture sorption and desorption curves of brucine HyC ↔ AH at 25 °C. (b) Moisture-dependent PXRD measurements of HyC. Numbers on the y axis indicate the moisture in % at which the powder pattern was recorded. Due to different equilibration times and other parameters such as sample amount, dynamics of the atmosphere, etc., the hydration rates in the gravimetric moisture chamber (GMS) are different from kinetics in the moisture stage (VGI) used for the PXRD recordings.
Figure 6
Figure 6. Raman spectra of brucine HyA as a function of time exposure to D2O vapor (∼98% RH). Peaks due to O–D stretching vibrations emerge over the course of a few hours and are highlighted in yellow.
Figure 7
Figure 7. Phase diagram after equilibration for 1 week showing the dependence of brucine solid forms on water activity/relative humidity at 10, 25, and 40 °C.
Figure 8
Figure 8. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of HyA. The TGA curve (i) was recorded in a pan covered with a one pinhole lid at a heating rate of 5 °C min–1. The DSC curves were recorded in pans with five pinhole lids and heating rates of 3 °C min–1 (ii) and 5 °C min–1 (iii and v), respectively, or a sealed pan (iv, v) at a heating rate of 5 °C min–1. (v) DSC curve of AH.
Figure 9
Figure 9. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of HyB. The TGA curve (i) was recorded in an open pan at a heating rate of 5 °C min–1. The DSC curves were recorded in open pans at heating rates of 2 °C min–1 (ii) and 5 °C min–1 (iii), respectively, or a sealed pan (iv, v), at a heating rate of 5 °C min–1. (v) DSC curve of amorphous brucine. Dashed ellipsoids in (ii, iii, and v) indicate the glass transition.
Figure 10
Figure 10. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of HyC. The TGA curve (i) was recorded in a pan covered with a one pinhole lid at a heating rate of 5 °C min–1. The DSC curves were recorded in pans with five (ii) or one (iii) pinhole lids and heating rates of 2 °C min–1 (ii) and 5 °C min–1 (iii and v), respectively, or a sealed pan (iv, v) at a heating rate of 5 °C min–1. (v) DSC curve of AH.
Figure 11
Figure 11. Flowcharts showing the dehydration (a), hydration (b), and interrelation pathways of brucine solid forms upon storage.
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- 19Rager, T.; Geoffroy, A.; Hilfiker, R.; Storey, J. M. D. Phys. Chem. Chem. Phys. 2012, 14, 8074– 8082 DOI: 10.1039/c2cp40128bThere is no corresponding record for this reference.
- 20Braun, D. E.; Gelbrich, T.; Kahlenberg, V.; Griesser, U. J. Mol. Pharmaceutics 2014, 11, 3145– 3163 DOI: 10.1021/mp500334z20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFOqtLnF&md5=c58066f23dd414cdba48d96802fdcb54Insights into Hydrate Formation and Stability of Morphinanes from a Combination of Experimental and Computational ApproachesBraun, Doris E.; Gelbrich, Thomas; Kahlenberg, Volker; Griesser, Ulrich J.Molecular Pharmaceutics (2014), 11 (9), 3145-3163CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Morphine, codeine, and ethylmorphine are important drug compds. whose free bases and hydrochloride salts form stable hydrates. These compds. were used to systematically investigate the influence of the type of functional groups, the role of water mols., and the Cl- counterion on mol. aggregation and solid state properties. Five new crystal structures have been detd. Addnl., structure models for anhyd. ethylmorphine and morphine hydrochloride dihydrate, two phases existing only in a very limited humidity range, are proposed on the basis of computational dehydration modeling. These match the exptl. powder X-ray diffraction patterns and the structural information derived from IR spectroscopy. All 12 structurally characterized morphinane forms (including structures from the Cambridge Structural Database) crystallize in the orthorhombic space group P212121. Hydrate formation results in higher dimensional hydrogen bond networks. The salt structures of the different compds. exhibit only little structural variation. Anhyd. polymorphs were detected for all compds. except ethylmorphine (one anhydrate) and its hydrochloride salt (no anhydrate). Morphine HCl forms a trihydrate and dihydrate. Differential scanning and isothermal calorimetry were employed to est. the heat of the hydrate ↔ anhydrate phase transformations, indicating an enthalpic stabilization of the resp. hydrate of 5.7 to 25.6 kJ mol-1 relative to the most stable anhydrate. These results are in qual. agreement with static 0 K lattice energy calcns. for all systems except morphine hydrochloride, showing the need for further improvements in quant. thermodn. prediction of hydrates having water···water interactions. Thus, the combination of a variety of exptl. techniques, covering temp.- and moisture-dependent stability, and computational modeling allowed us to generate sufficient kinetic, thermodn. and structural information to understand the principles of hydrate formation of the model compds. This approach also led to the detection of several new crystal forms of the investigated morphinanes.
- 21Braun, D. E.; Koztecki, L. H.; McMahon, J. A.; Price, S. L.; Reutzel-Edens, S. M. Mol. Pharmaceutics 2015, 12, 3069– 3088 DOI: 10.1021/acs.molpharmaceut.5b0035721https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVShtLrM&md5=03aa5a9f0b1132241db993afd8d16e81Navigating the Waters of Unconventional Crystalline HydratesBraun, Doris E.; Koztecki, Lien H.; McMahon, Jennifer A.; Price, Sarah L.; Reutzel-Edens, Susan M.Molecular Pharmaceutics (2015), 12 (8), 3069-3088CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Elucidating the crystal structures, transformations, and thermodn. of the two zwitterionic hydrates (Hy2 and HyA) of 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoicacid(DB7) rationalizes the complex interplay of temp., water activity, and pH on the solid form stability and transformation pathways to three neutral anhydrate polymorphs (Forms I, II°, and III). HyA contains 1.29 to 1.95 mols. of water per DB7 zwitterion (DB7z). Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°. Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions. X-ray crystallog., solid state NMR, and H/D exchange expts. on highly cryst. phase pure samples obtained by exquisite control over crystn., filtration, and drying conditions, along with computational modeling, provided a mol. level understanding of this system. The slow rates of many transformations and sensitivity of equil. to exact conditions, arising from its varying static and dynamic disorder and water mobility in different phases, meant that characterizing DB7 hydration in terms of simplified hydrate classifications was inappropriate for developing this pharmaceutical.
- 22Bernardes, C. E. S.; da Piedade, M. E. M. Cryst. Growth Des. 2012, 12, 2932– 2941 DOI: 10.1021/cg300134z22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xnt1Wqu7Y%253D&md5=f9fb28f074e1fa5138b7ec4940ddbce1Crystallization of 4'-Hydroxyacetophenone from Water: Control of Polymorphism via Phase Diagram StudiesBernardes, Carlos E. S.; da Piedade, Manuel E. MinasCrystal Growth & Design (2012), 12 (6), 2932-2941CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)The prepn. of polymorphs and solvates and the characterization of their stability domains have received considerable attention in recent years, due to the importance of these studies for fundamental research and for the prodn. of new materials for task-specific applications. In this work, the selective and reproducible crystn. of different solid forms of 4'-hydroxyacetophenone (HAP) from water was investigated, through the detn. of a temp.-concn. (T-cHAP) phase diagram. This detn. was mainly based on gravimetric soly. measurements, slurry tests, and metastable zone width (MZW) studies with thermometric and turbidity detection. The exptl. conditions for the formation of five different HAP phases by cooling crystn. could be established: the previously characterized anhyd. forms I and II and the hydrate HAP·1.5H2O (H1), and two new hydrates, one of stoichiometry HAP·3H2O (H2) and another (H3) which proved too unstable for a stoichiometry detn. The crystn. precedence of the various phases, their approx. lifetimes, and transformation sequences could also be elucidated. It was finally found that for a specific T-cHAP domain the crystn. of HAP solid phases was mediated by a colloidal dispersion. Preliminary dynamic light scattering expts. indicated that this dispersion consisted of particles with diams. in the range of 100-800 nm.
- 23Pina, M. F.; Pinto, J. F.; Sousa, J. J.; Fabian, L.; Zhao, M.; Craig, D. Q. M. Mol. Pharmaceutics 2012, 9, 3515– 3525 DOI: 10.1021/mp300357323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVyltbbN&md5=55d9efc8e5d3897053dc23abde4f290dIdentification and Characterization of Stoichiometric and Nonstoichiometric Hydrate Forms of Paroxetine HCl: Reversible Changes in Crystal Dimensions as a Function of Water AbsorptionPina, M. Fatima; Pinto, Joao F.; Sousa, Joao J.; Fabian, Laszlo; Zhao, Min; Craig, Duncan Q. M.Molecular Pharmaceutics (2012), 9 (12), 3515-3525CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Paroxetine hydrochloride (HCl) is an antidepressant drug, reported to exist in the anhyd. form (form II) and as a stable hemihydrate (form I). In this study, we investigate the hydration behavior of paroxetine HCl form II with a view to understanding both the nature of the interaction with water and the interchange between forms II and I as a function of both temp. and water content. In particular, we present new evidence for both the structure and the interconversion process to be more complex than previously recognized. A combination of characterization techniques was used, including thermal (differential scanning calorimetry (DSC) and thermogravimetric anal. (TGA)), spectroscopic (attenuated total reflectance Fourier transform IR spectroscopy (ATR-FTIR)), dynamic vapor sorption (DVS) and X-ray powder diffraction (XRPD) with variable humidity, along with computational mol. modeling of the crystal structures. The total amt. of water present in form II was surprisingly high (3.8% wt./wt., 0.8 mol of water/mol of drug), with conversion to the hemihydrate noted on heating in hermetically sealed DSC pans. XRPD, supported by ATR-FTIR and DVS, indicated changes in the unit cell dimensions as a function of water content, with clear evidence for reversible expansion and contraction as a function of relative humidity (RH). Based on these data, we suggest that paroxetine HCl form II is not an anhydrate but rather a nonstoichiometric hydrate. However, no continuous channels are present and, according to mol. modeling simulation, the water is moderately strongly bonded to the crystal, which is in itself an uncommon feature when referring to nonstoichiometric hydrates. Overall, therefore, we suggest that the anhyd. form of paroxetine HCl is not only a nonstoichiometric hydrate but also one that shows highly unusual characteristics in terms of gradual unit cell expansion and contraction despite the absence of continuous channels. These structural features in turn influence the tendency of this drug to convert to the more stable hemihydrate. The study has implications for the recognition and understanding of the behavior of pharmaceutical nonstoichiometric hydrates.
- 24Stephenson, G. A.; Diseroad, B. A. Int. J. Pharm. 2000, 198, 167– 177 DOI: 10.1016/S0378-5173(00)00331-824https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXitlelurg%253D&md5=c35a958fdeb5bf32e34590b90a180407Structural relationship and desolvation behavior of cromolyn, cefazolin and fenoprofen sodium hydratesStephenson, G. A.; Diseroad, B. A.International Journal of Pharmaceutics (2000), 198 (2), 167-177CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)The hydrated crystal structures of cromolyn, cefazolin, and fenoprofen sodium salts are reported. The former two compds. are non-stoichiometric hydrates, whereas the fenoprofen lattice maintains its stoichiometry over a broad range of relative humidity. The relationship between compn., lattice parameters, and relative humidity is studied using a combination of moisture sorption isotherms and variable humidity X-ray powder diffraction. The dehydration properties of the sodium salts are related to the ion coordination and hydrogen bonding of the water mols. in the structures. Anisotropic lattice contraction is obsd. during dehydration of the cromolyn and cefazolin sodium and is related to the closeness of intermol. contacts in the hydrated structures.
- 25Berzins, A.; Skarbulis, E.; Rekis, T.; Actins, A. Cryst. Growth Des. 2014, 14, 2654– 2664 DOI: 10.1021/cg500344725https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmtlSgtL8%253D&md5=cc3bdefbbc3b5536a7d8d5f9bfec6e72On the Formation of Droperidol Solvates: Characterization of Structure and PropertiesBerzins, Agris; Skarbulis, Edgards; Rekis, Toms; Actins, AndrisCrystal Growth & Design (2014), 14 (5), 2654-2664CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)A solvate screening and characterization of the obtained solvates was performed to rationalize and understand the solvate formation of active pharmaceutical ingredient droperidol (1-{1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydro-4-pyridyl}-1,3-dihydro-2H-benzimidazol-2-one). The solvate screening revealed that droperidol can form 11 different solvates. The anal. of the crystal structures and mol. properties revealed that droperidol solvate formation is mainly driven by the inability of droperidol mols. to pack efficiently. The obtained droperidol solvates were characterized by x-ray diffraction and thermal anal. Droperidol forms 7 nonstoichiometric isostructural solvates, and the crystal structures were detd. for 5 of these solvates. To better understand the structure of these 5 solvates, their solvent sorption-desorption isotherms were recorded, and lattice parameter dependence on the solvent content was detd. This revealed a different behavior of the nonstoichiometic hydrate, which was explained by the simultaneous insertion of 2 H-bonded H2O mols. Isostructural solvates were formed with sufficiently small solvent mols. providing effective intermol. interactions, and solvate formation was rationalized based on already presented solvent classification. The lack of solvent specificity in isostructural solvates was explained by the very effective interactions between droperidol mols. Desolvation of stoichiometric droperidol solvates produced 1 of the 4 droperidol polymorphs, whereas that of nonstoichiometic solvates produced an isostructural desolvate. Crystallog. data are given.
- 26Campeta, A. M.; Chekal, B. P.; Abramov, Y. A.; Meenan, P. A.; Henson, M. J.; Shi, B.; Singer, R. A.; Horspool, K. R. J. Pharm. Sci. 2010, 99, 3874– 3886 DOI: 10.1002/jps.2223026https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXptlejsbw%253D&md5=98fc54e1d2ff0cf2e79bfc0807cec36bDevelopment of a targeted polymorph screening approach for a complex polymorphic and highly solvating APICampeta, Anthony M.; Chekal, Brian P.; Abramov, Yuriy A.; Meenan, Paul A.; Henson, Mark J.; Shi, Bing; Singer, Robert A.; Horspool, Keith R.Journal of Pharmaceutical Sciences (2010), 99 (9), 3874-3886CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)Elucidation of the most stable form of an active pharmaceutical ingredient (API) is a crit. step in the development process. Polymorph screening for an API with a complex polymorphic profile can present a significant challenge. The presented case illustrates an extensively polymorphic compd. with an addnl. propensity for forming stable solvates. In all, 5 anhyd. forms and 66 solvated forms have been discovered. After early polymorph screening using common techniques yielded mostly solvates and failed to uncover several key anhyd. forms, it became necessary to devise new approaches based on an advanced understanding of crystal structure and conformational relationships between forms. With the aid of this anal., two screening approaches were devised which targeted high-temp. desolvation as a means to increase conformational populations and enhance overall probability of anhyd. form prodn. Application of these targeted approaches, comprising over 100 expts., produced only the known anhyd. forms, without appearance of any new forms. The development of these screens was a crit. and alternative approach to circumvent solvation issues assocd. with more conventional screening methods. The results provided confidence that the current development form was the most stable polymorph, with a low likelihood for the existence of a more-stable anhyd. form. © 2010 Wiley-Liss, Inc. and the American Pharmacists Assocn. J Pharm Sci 99:3874-3886, 2010.
- 27Zhao, X. S.; Siepmann, J. I.; Xu, W.; Kiang, Y. H.; Sheth, A. R.; Karaborni, S. J. Phys. Chem. B 2009, 113, 5929– 5937 DOI: 10.1021/jp808164tThere is no corresponding record for this reference.
- 28Morissette, S. L.; Almarsson, O.; Peterson, M. L.; Remenar, J. F.; Read, M. J.; Lemmo, A. V.; Ellis, S.; Cima, M. J.; Gardner, C. R. Adv. Drug Delivery Rev. 2004, 56, 275– 300 DOI: 10.1016/j.addr.2003.10.020There is no corresponding record for this reference.
- 29Aaltonen, J.; Alleso, M.; Mirza, S.; Koradia, V.; Gordon, K. C.; Rantanen, J. Eur. J. Pharm. Biopharm. 2009, 71, 23– 37 DOI: 10.1016/j.ejpb.2008.07.01429https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsV2lurbF&md5=f7296a912891c6e96d6cb42a351a6478Solid form screening - A reviewAaltonen, Jaakko; Alleso, Morten; Mirza, Sabiruddin; Koradia, Vishal; Gordon, Keith C.; Rantanen, JukkaEuropean Journal of Pharmaceutics and Biopharmaceutics (2009), 71 (1), 23-37CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)A review. Solid form screening, the activity of generating and analyzing different solid forms of an active pharmaceutical ingredient (API), has become an essential part of drug development. The multi-step screening process needs to be designed, performed and evaluated carefully, since the decisions made based on the screening may have consequences on the whole lifecycle of a pharmaceutical product. The selection of the form for development is made after solid form screening. The selection criteria include not only pharmaceutically relevant properties, such as therapeutic efficacy and processing characteristics, but also intellectual property (IP) issues. In this paper, basic principles of solid form screening are reviewed, including the methods used in exptl. screening (generation, characterization and anal. of solid forms, data mining tools, and high-throughput screening technologies) as well as basics of computational methods. Differences between solid form screening strategies of branded and generic pharmaceutical manufacturers are also discussed.
- 30Allesoe, M.; Tian, F.; Cornett, C.; Rantanen, J. J. Pharm. Sci. 2010, 99, 3711– 3718 DOI: 10.1002/jps.21957There is no corresponding record for this reference.
- 31Rasanen, E.; Rantanen, J.; Jorgensen, A.; Karjalainen, M.; Paakkari, T.; Yliruusi, J. J. Pharm. Sci. 2001, 90, 389– 396 DOI: 10.1002/1520-6017(200103)90:3<389::AID-JPS13>3.0.CO;2-9There is no corresponding record for this reference.
- 32Wikstroem, H.; Kakidas, C.; Taylor, L. S. J. Pharm. Biomed. Anal. 2009, 49, 247– 252 DOI: 10.1016/j.jpba.2008.11.00832https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhs1alsr4%253D&md5=719cac492bf441cc02789b9ab7975f7fDetermination of hydrate transition temperature using transformation kinetics obtained by Raman spectroscopyWikstroem, Hakan; Kakidas, Christopher; Taylor, Lynne S.Journal of Pharmaceutical and Biomedical Analysis (2009), 49 (2), 247-252CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)The thermodn. transition temp. is a key parameter to ascertain when assessing the properties of a cryst. hydrate. The transition temp. is sometimes difficult to det. exptl. due to rapid transformation between the two crystal forms in soln. In this study, a new approach for detg. the transition temp. is presented, utilizing the temp. dependence of the transformation kinetics in aq. slurries, as detd. using in-line Raman spectroscopy. The transition temps. of several hydrate forming compds., namely theophylline, carbamazepine and caffeine, are presented. In general, good correlations with literature values were found. This method was found to be a simple, fast and reliable approach for the detn. of crystal hydrate transition temps. in aq. environments.
- 33Morris, K. R.; Griesser, U. J.; Eckhardt, C. J.; Stowell, J. G. Adv. Drug Delivery Rev. 2001, 48, 91– 114 DOI: 10.1016/S0169-409X(01)00100-4There is no corresponding record for this reference.
- 34Tantry, J. S.; Tank, J.; Suryanarayanan, R. J. Pharm. Sci. 2007, 96, 1434– 1444 DOI: 10.1002/jps.20746There is no corresponding record for this reference.
- 35Debnath, S.; Suryanarayanan, R. AAPS PharmSciTech 2004, 5, 39 DOI: 10.1208/pt050108There is no corresponding record for this reference.
- 36Chakravarty, P.; Suryanarayanan, R.; Govindarajan, R. J. Pharm. Sci. 2012, 101, 1410– 1422 DOI: 10.1002/jps.23020There is no corresponding record for this reference.
- 37Griesser, U. J. In Polymorphism: In the Pharmaceutical Industry; Hilfiker, R., Ed.; Wiley-VCH: Weinheim, Germany, 2006; pp 211– 233.There is no corresponding record for this reference.
- 38Te, R. L.; Griesser, U. J.; Morris, K. R.; Byrn, S. R.; Stowell, J. G. Cryst. Growth Des. 2003, 3, 997– 1004 DOI: 10.1021/cg034074938https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmt1Kkurw%253D&md5=3bbc0c300056ae33115a5e58af3d1811X-ray Diffraction and Solid-State NMR Investigation of the Single-Crystal to Single-Crystal Dehydration of Thiamine Hydrochloride MonohydrateTe, Ruth L.; Griesser, Ulrich J.; Morris, Kenneth R.; Byrn, Stephen R.; Stowell, Joseph G.Crystal Growth & Design (2003), 3 (6), 997-1004CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)The dehydration of a thiamine hydrochloride (vitamin B1) hydrate, commonly referred to as the monohydrate, was investigated by solid-state NMR (SSNMR) and X-ray diffraction (XRD) techniques. The hydrate can be classified as a nonstoichiometric solvate since the water content depends on the water vapor pressure of the surrounding atm. and essentially maintains the three-dimensional mol. arrangement upon dehydration. Thus, we were able to det. the crystal structures of both the hydrate and the isomorphic desolvate with one single crystal. The loss of water leads to a shrinkage of the unit cell vol. of about 5% and to a slight increase in the free vol. This is also accompanied by an increase in mol. motion as is demonstrated by SSNMR 1H and 13C T1 measurements. The largest change in T1 was obsd. for the carbons of the hydroxyethyl functional group that is hydrogen bonded to the water mols. in the hydrate. This investigation confirms that an increase in free vol. results in an increase in mol. mobility and demonstrates the impact of mol. interactions on the mobility of specific mol. entities.
- 39Otsuka, M.; Kaneniwa, N. Yakugaku Zasshi 1982, 102, 359– 364There is no corresponding record for this reference.
- 40Bauer, J.; Quick, J.; Oheim, R. J. Pharm. Sci. 1985, 74, 899– 900 DOI: 10.1002/jps.2600740823There is no corresponding record for this reference.
- 41Byrn, S. R.; Sutton, P. A.; Tobias, B.; Frye, J.; Main, P. J. Am. Chem. Soc. 1988, 110, 1609– 1614 DOI: 10.1021/ja00213a039There is no corresponding record for this reference.
- 42Stephenson, G. A.; Groleau, E. G.; Kleemann, R. L.; Xu, W.; Rigsbee, D. R. J. Pharm. Sci. 1998, 87, 536– 542 DOI: 10.1021/js970449zThere is no corresponding record for this reference.
- 43Mimura, H.; Kitamura, S.; Kitagawa, T.; Kohda, S. Colloids Surf., B 2002, 26, 397– 406 DOI: 10.1016/S0927-7765(02)00026-7There is no corresponding record for this reference.
- 44The Merck Index, 14th ed. [Online]; Merck Inc.: Whitehouse Station, NJ, 2006.There is no corresponding record for this reference.
- 45Gould, R. O.; Walkinshaw, M. D. J. Am. Chem. Soc. 1984, 106, 7840– 7842 DOI: 10.1021/ja00337a031There is no corresponding record for this reference.
- 46Quinkert, G.; Schmalz, H. G.; Dzierzynski, E. M.; Duerner, G.; Bats, J. W. Angew. Chem. 1986, 98, 1023– 1024 DOI: 10.1002/ange.19860981126There is no corresponding record for this reference.
- 47Boiadjiev, S. E.; Person, R. V.; Puzicha, G.; Knobler, C.; Maverick, E.; Trueblood, K. N.; Lightner, D. A. J. Am. Chem. Soc. 1992, 114, 10123– 10133 DOI: 10.1021/ja00052a006There is no corresponding record for this reference.
- 48Dijksma, F. J. J.; Gould, R. O.; Parsons, S.; Taylor, P.; Walkinshaw, M. D. Chem. Commun. 1998, 745– 746 DOI: 10.1039/a800219cThere is no corresponding record for this reference.
- 49Agrawal, S. S.; Saraswati, S.; Mathur, R.; Pandey, M. Life Sci. 2011, 89, 147– 158 DOI: 10.1016/j.lfs.2011.05.020There is no corresponding record for this reference.
- 50Chen, H. b.; Ma, F. s.; Fang, J. q.; Fang, F. Zhongchengyao 2015, 37, 16– 2150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1alsrnF&md5=6660dc562b1aa4e387c43ab289e01de8Cytotoxicity of components from seeds of Strychnos nuxvomica to human HaCaT keratinocytesChen, Hai-bo; Ma, Feng-sen; Fang, Jian-qiao; Fang, FangZhongchengyao (2015), 37 (1), 16-21CODEN: ZHONBS; ISSN:1001-1528. (Zhongchengyao Zazhi Bianjibu)The purpose of the research is to study the cytotoxicity of alkaloids from Strychni Semen and its different components on HaCaT cell, an immortalized human epidermal cell line. In vitro cultured HaCaT cells co-cultured with same concns. of brucine, strychnine, and the mixt. of brucine and strychnine, total alkaloids from Strychni Semen for 24 h, the no. of viable cells was obsd. by using the MTT method. The cell apoptotic rate was detected and calcd. by flow cytometry. Cytotoxicity on HaCaT cell was compared among different components of alkaloids from Strychni Semen. The proliferation rates and the apoptotic rate of strychnine on HaCaT were greater than brucine at the same concn., the mixt. of brucine and strychnine on HaCaT were greater than total alkaloids from Strychni Semen similarly in those two rates. The components of alkaloids from Strychni Semen have obvious cytotoxicity to HaCaT cell in a dose-dependent relationship, meanwhile, cytotoxicity of brucine is lower than that of strychnine.
- 51Deng, X. K.; Yin, W.; Li, W. D.; Yin, F. Z.; Lu, X. Y.; Zhang, X. C.; Hua, Z. C.; Cai, B. C. J. Ethnopharmacol. 2006, 106, 179– 186 DOI: 10.1016/j.jep.2005.12.021There is no corresponding record for this reference.
- 52Yin, W.; Deng, X. K.; Yin, F. Z.; Zhang, X. C.; Cai, B. C. Food Chem. Toxicol. 2007, 45, 1700– 1708 DOI: 10.1016/j.fct.2007.03.00452https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXot12ksrs%253D&md5=c6d067d8e0b29ecdf7767cd916e8f0e7The cytotoxicity induced by brucine from the seed of Strychnos nux-vomica proceeds via apoptosis and is mediated by cyclooxygenase 2 and caspase 3 in SMMC 7221 cellsYin, Wu; Deng, Xu-Kun; Yin, Fang-Zhou; Zhang, Xiao-Chun; Cai, Bao-ChangFood and Chemical Toxicology (2007), 45 (9), 1700-1708CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)To study the cytotoxicity of four alkaloids: brucine, strychnine, brucine N-oxide and isostrychnine from nux vomica on SMMC 7721 cells and their possible mechanisms, MET assay was used to examine the growth inhibitory effects of these alkaloids. Brucine revealed the strongest growth inhibitory effect on SMMC-7721 cells. Furthermore, as directly obsd. under an inverted microscope, fluorescent microscope and transmission electronic microscope, brucine caused SMMC-7721 cell shrinkage, membrane blobbing, formation of apoptotic body as well as nucleus condensation, all of which are typical characteristics of apoptotic programmed cell death. In addn., brucine dose-dependently caused SMMC-7721 cells apoptosis via formation of subdipolid DNA and phosphatidylserine externalization, as evidenced by flow cytometry anal. The brucine-induced apoptosis was partially attributed to the activation of caspase 3 as well as cyclooxygenase 2 inhibition, since neither caspase 3 specific inhibitor, z-DEVD-fmk nor was exogenous addn. of prostaglandin E2 able to completely abrogate the brucine-induced SMMC 7721 cell apoptosis. In sum, this paper indicate that the major alkaloids present in the seed of Strychnos nux-vomica are effective against SMMC-7721 cells proliferation, among which brucine proceeds SMMC-7721 cells death via apoptosis, probably through the participation of caspase 3 and cyclooxygenase 2.
- 53Rao, P. S.; Ramanadham, M.; Prasad, M. N. V. Food Chem. Toxicol. 2009, 47, 283– 288 DOI: 10.1016/j.fct.2008.10.02753https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotl2ksA%253D%253D&md5=267bc1bffd8e25651e16e1053b98ffd3Anti-proliferative and cytotoxic effects of Strychnos nux-vomica root extract on human multiple myeloma cell line - RPMI 8226Rao, Pasupuleti Sreenivasa; Ramanadham, Madduri; Prasad, Majeti Narasimha VaraFood and Chemical Toxicology (2009), 47 (2), 283-288CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)Multiple myeloma (MM) is an incurable hematol. malignancy with high incidence in the elderly. The currently used chemotherapeutic drugs show severe side effects, dose-limiting toxicity and development of resistance. In search of novel plant derived anti-cancer agents, Strychnos nux-vomica L. (SN) root ext. was screened using the human MM-cell line, RPMI 8226. SN-ext. exhibited anti-proliferative activity in a dose and time dependent manner. The morphol. assessment of SN-ext. treated cells showed significant features assocd. with apoptosis. Cell cycle anal. using flow cytometry of cells stained with propidium iodide revealed accumulation of cells at sub-G0/G1 phase. In addn., disruption of mitochondrial membrane potential and subsequent leakage of mitochondrial cytochrome c was obsd. in SN-ext. treated myeloma cells. The anti-proliferative and cytotoxic activity could be due to the alkaloids strychnine and brucine, which have been identified by LC-mass spectral anal. of the SN-ext. in comparison to the ref. stds. analyzed under identical conditions.
- 54Chen, J.; Wang, X.; Qu, Y. g.; Chen, Z. p.; Cai, H.; Liu, X.; Xu, F.; Lu, T. l.; Cai, B. C. J. Ethnopharmacol. 2012, 139, 181– 188 DOI: 10.1016/j.jep.2011.10.038There is no corresponding record for this reference.
- 55Groth, P. Chemische Krystallographie. Teil 5. Aromatische Kohlenstoffverbindungen mit mehreren Benzolringen heterocyclische Verbindungen; W. Engelmann: Leipzig, Germany, 1919; Vol. 5.There is no corresponding record for this reference.
- 56Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C. Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 2016, 72, 171– 179 DOI: 10.1107/S205252061600395456https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xls1Kntro%253D&md5=f9c65ab86fc9db429588c95b0da3f9b2The Cambridge Structural DatabaseGroom, Colin R.; Bruno, Ian J.; Lightfoot, Matthew P.; Ward, Suzanna C.Acta Crystallographica, Section B: Structural Science, Crystal Engineering and Materials (2016), 72 (2), 171-179CODEN: ACSBDA; ISSN:2052-5206. (International Union of Crystallography)The Cambridge Structural Database (CSD) contains a complete record of all published org. and metal-org. small-mol. crystal structures. The database has been in operation for over 50 years and continues to be the primary means of sharing structural chem. data and knowledge across disciplines. As well as structures that are made public to support scientific articles, it includes many structures published directly as CSD Communications. All structures are processed both computationally and by expert structural chem. editors prior to entering the database. A key component of this processing is the reliable assocn. of the chem. identity of the structure studied with the exptl. data. This important step helps ensure that data is widely discoverable and readily reusable. Content is further enriched through selective inclusion of addnl. exptl. data. Entries are available to anyone through free CSD community web services. Linking services developed and maintained by the CCDC, combined with the use of std. identifiers, facilitate discovery from other resources. Data can also be accessed through CCDC and third party software applications and through an application programming interface.
- 57Bialonska, A.; Ciunik, Z. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2004, 60, o853– o855 DOI: 10.1107/S010827010402487457https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVeku7zP&md5=2db2ebdbf91fe44236c50732bf33e10aBrucine and two solvatesBialonska, Agata; Ciunik, ZbigniewActa Crystallographica, Section C: Crystal Structure Communications (2004), C60 (12), o853-o855CODEN: ACSCEE; ISSN:0108-2701. (Blackwell Publishing Ltd.)The crystal structures of brucine (2,3-dimethoxystrychnidin-10-one), C23H26N2O4, brucine acetone solvate, C23H26N2O4·C3H6O, and brucine iso-PrOH solvate dihydrate, C23H26N2O4·C3H7O·2H2O, were detd. Crystallog. data are given. Crystals of brucine and its iso-PrOH solvate dihydrate exhibit similar monolayer sheet packing, whereas crystals of the acetone solvate adopt a different mode of packing, as brucine pillars. The solvent appears to control the brucine self-assembly from common donor-acceptor properties of the surfaces.
- 58Bialonska, A.; Ciunik, Z.; Ilczyszyn, M. M.; Siczek, M. Cryst. Growth Des. 2014, 14, 6537– 6541 DOI: 10.1021/cg501437g58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFWjs7%252FK&md5=d04e2f38b80855fd451c3909437f5087Discrete Cuboidal 15- and 16-Membered Water Clusters in Brucine 3.86-Hydrate, Water Release and Its ConsequencesBialonska, Agata; Ciunik, Zbigniew; Ilczyszyn, Maria M.; Siczek, MiloszCrystal Growth & Design (2014), 14 (12), 6537-6541CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)Up to now, three brucine hydrates are known, brucine di-, tetra-, and 5.25-hydrate. All of them were obtained from solns. contg. the additive diethanolamine, adenosine, and urea, resp. Studying the role of the additives on crystn. of the brucine hydrates, the authors obtained a new, kinetically favored brucine 3.86-hydrate. In crystals of brucine 3.86-hydrate, large 15- and 16-membered water clusters of cuboidal topol. are encapsulated in cages formed between honeycomb-like brucine layers. Dehydration of the brucine hydrate leads to formation of the known anhyd. brucine, giving insight into a mechanism of the dehydration process, in which a shift of brucine ribbons in the honeycomb-like layers leads to an opening of channels and water release. A collapse of brucine layers after the water release results in formation of the common anhyd. brucine. The anhyd. brucine undergoes a phase transition at 249 K in the cooling mode and at 277 K in the heating mode. The phase transition is attributable to a huge shift of brucine corrugated layers in relation to each other. The phase transition for anhyd. brucine obtained by dehydration is accompanied by thermal effects one order larger than anhyd. brucine, obtained by crystn. from acetone soln.
- 59Smith, G.; Wermuth, U. D.; White, J. M. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2007, 63, o489– o492 DOI: 10.1107/S010827010703229559https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosVKnsrc%253D&md5=a552f10c893d6f8930ed2964d4d362c4Pseudopolymorphism in brucine: brucine-water (1/2), the third crystal hydrate of brucineSmith, Graham; Wermuth, Urs D.; White, Jonathan M.Acta Crystallographica, Section C: Crystal Structure Communications (2007), 63 (8), o489-o492CODEN: ACSCEE; ISSN:0108-2701. (International Union of Crystallography)The structure of a 3rd pseudopolymorphic hydrate of brucine, brucine-H2O (1/2) [systematic name: 2,3-dimethoxystrychnidin-10-one-H2O (1/2)], C23H26N2O4·2H2O, was detd. at 130 K. Crystallog. data are given. The asym. unit comprises two independent brucine mols. and four H2O mols. of solvation. The four H2O mols. form uncommon cyclic H-bonded homomol. R44(8) tetramer rings, which then form primary H-bonded chain substructures extending down the 21 screw axis in the unit cell. The two brucine mols. are linked peripherally to these substructures by either single O-H···Nbrucine or asym. three-center O-H···Obrucine H bonds.
- 60Smith, G.; Wermuth, U. D.; Healy, P. C.; White, J. M. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2006, 62, o203– o207 DOI: 10.1107/S010827010600594460https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjtFOqsb0%253D&md5=dc824374ec8287ab24080150b3d53ed7Two pseudopolymorphic hydrates of brucine: brucine-water (1/4) and brucine-water (1/5.25) at 130 KSmith, Graham; Wermuth, Urs D.; Healy, Peter C.; White, Jonathan M.Acta Crystallographica, Section C: Crystal Structure Communications (2006), C62 (4), o203-o207CODEN: ACSCEE; ISSN:0108-2701. (Blackwell Publishing Ltd.)The structures of two pseudopolymorphic hydrates of brucine, C23H26N2O4·4H2O, (I), and C23H26N2O4·5.25H2O, (II), were detd. at 130 K. In both (I) and (II) (which has two independent brucine mols. together with 10.5 H2O mols. of solvation in the asym. unit), the brucine mols. form head-to-tail sheet substructures, which assoc. with the H2O mols. in the interstitial cavities through H-bonding assocns. and, together with water-H2O assocns., give three-dimensional framework structures.
- 61Watabe, T.; Kobayashi, K.; Hisaki, I.; Tohnai, N.; Miyata, M. Bull. Chem. Soc. Jpn. 2007, 80, 464– 475 DOI: 10.1246/bcsj.80.464There is no corresponding record for this reference.
- 62Glover, S. S. B.; Gould, R. O.; Walkinshaw, M. D. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1985, 41, 990– 994 DOI: 10.1107/S0108270185006308There is no corresponding record for this reference.
- 63Bialonska, A.; Ciunik, Z. CrystEngComm 2013, 15, 5681– 5687 DOI: 10.1039/c3ce40512eThere is no corresponding record for this reference.
- 64Goelles, F. Monatsh. Chem. 1961, 92, 981– 991 DOI: 10.1007/BF0092476364https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF38XlslOjsQ%253D%253D&md5=67008f5c8c1028b8f0306fcd6334fff0The examination and calculation of thermodynamic data from experimental measurements. I. The numerical integration of the vapor-pressure curves of the system methanol-waterGoelles, F.Monatshefte fuer Chemie (1961), 92 (), 981-91CODEN: MOCMB7; ISSN:0026-9247.The vapor-pressure curves of the system (Butler, et al., CA 27, 4464) were checked for thermodynamic consistency by the independent methods of Runge (Collatz, Numerische Behandlung yon Differentialgleichungen, 1951, Springer, Berlin) and Musil and Breitenhuber (CA 48, 4274h), and the activity coeffs. were recalcd. The calcd. values of the vapor-phase compn. lie between the exptl. values of Butler, et al. (loc. tit.) and those of Froemke, et al. (CA 28, 3918). The calcd. activity coeffs. of water (f1) and MeOH (f2) are given at the following mole fractions of MeOH: 0.1, 1.580, 0.994; 0.2, 1.461, 1.036; 0.3, 1.303, 1.068; 0.4, 1.175, 1.090; 0.5, 1.118, 1.139; 0.6, 1.068, 1.160; 0.7, 1.050, 1.192; 0.8, 1.025, 1.270; 0.9, 1.010, 1.479. The max. discrepancy between f1 exptl. and f1 calcd. is 10%, when x = 0.1.
- 65Zhu, H.; Yuen, C.; Grant, D. J. W. Int. J. Pharm. 1996, 135, 151– 160 DOI: 10.1016/0378-5173(95)04466-365https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjsVOqsr0%253D&md5=e70cda80586c4da5fc96df6c0417fe01Influence of water activity in organic solvent + water mixtures on the nature of the crystallizing drug phase. 1. TheophyllineZhu, Haijian; Yuen, Ceaminia; Grant, David J. W.International Journal of Pharmaceutics (1996), 135 (1,2), 151-160CODEN: IJPHDE; ISSN:0378-5173. (Elsevier)The hydration state of a hydrate depends on the water activity, aw, in the crystn. medium. Selection of an appropriate ratio of water to cosolvent in the crystn. medium of a hydrate is crit. and is often semi-empirical. This study attempts to elucidate this selection process by studying the conditions of phys. stability of the solid phases of theophylline, which comprise an anhydrate and a monohydrate. A mixt. of the anhydrate and the monohydrate may sometimes be obtained, if the system is not in equil. The excess solid phase was characterized by powder X-ray diffractometry and the water content was measured by Karl-Fischer titrimetry. In contact with methanol + water or 2-propanol (iso-Pr alc., IPA) + water mixts., at aw<0.25, the anhydrate was the only solid phase at equil., no matter which solid form was initially added. At aw>0.25 in either solvent mixt., the monohydrate was obtained as the most stable form at equil. These results suggest (a) that water activity is the major factor detg. the nature of the solid phase of theophylline which crystallizes from methanol + water or IPA + water mixts. and (b) that the system, theophylline anhydrate .dblharw. theophylline monohydrate, is in equil. at aw = 0.25 and at 25°C. The solubilities of the two solid forms in each of the mixed solvent systems were also measured and are discussed. The concepts presented, tested and discussed may, in principle, be applied to any pharmaceutical system consisting of an anhydrate and a hydrate, or a lower hydrate and a higher hydrate.
- 66Aspen Properties, version 8.4; Aspen Technology, Inc.: Bedford, MA, 2015.There is no corresponding record for this reference.
- 67Markvardsen, A. J.; David, W. I. F.; Johnson, J. C.; Shankland, K. Acta Crystallogr., Sect. A: Found. Crystallogr. 2001, 57, 47– 54 DOI: 10.1107/S010876730001217467https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXovF2nsLs%253D&md5=8a0c6a09ce2d11ab9af12e5a8369a8a5A probabilistic approach to space-group determination from powder diffraction dataMarkvardsen, A. J.; David, W. I. F.; Johnston, J. C.; Shankland, K.Acta Crystallographica, Section A: Foundations of Crystallography (2001), A57 (1), 47-54CODEN: ACACEQ; ISSN:0108-7673. (Munksgaard International Publishers Ltd.)An algorithm for the detn. of the space-group symmetry of a crystal from powder diffraction data, based upon probability theory, is described. Specifically, the relative probabilities of different extinction symbols are assessed within a particular crystal system. In general, only a small no. of extinction symbols are relatively highly probable and a single extinction symbol is often significantly more probable than any other. Several examples are presented to illustrate this approach.
- 68David, W. I. F.; Shankland, K.; van de Streek, J.; Pidcock, E.; Motherwell, W. D. S.; Cole, J. C. J. Appl. Crystallogr. 2006, 39, 910– 915 DOI: 10.1107/S002188980604211768https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1KrurjK&md5=ff86f9794641c07a843f9b28a1761865DASH. A program for crystal structure determination from powder diffraction dataDavid, William I. F.; Shankland, Kenneth; van de Streek, Jacco; Pidcock, Elna; Motherwell, W. D. Samuel; Cole, Jason C.Journal of Applied Crystallography (2006), 39 (6), 910-915CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)DASH is a user-friendly graphical-user-interface-driven computer program for solving crystal structures from X-ray powder diffraction data, optimized for mol. structures. Algorithms for multiple peak fitting, unit-cell indexing and space-group detn. are included as part of the program. Mol. models can be read in a no. of formats and automatically converted to Z-matrixes in which flexible torsion angles are automatically identified. Simulated annealing is used to search for the global min. in the space that describes the agreement between obsd. and calcd. structure factors. The simulated annealing process is very fast, which in part is due to the use of correlated integrated intensities rather than the full powder pattern. Automatic minimization of the structures obtained by simulated annealing and automatic overlay of solns. assist in assessing the reproducibility of the best soln., and therefore in detg. the likelihood that the global min. was obtained.
- 69Pawley, G. S. J. Appl. Crystallogr. 1981, 14, 357– 361 DOI: 10.1107/S002188988100961869https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38XhtlylsA%253D%253D&md5=56e059d8b778190e1f9e9076b68abf96Unit-cell refinement from powder diffraction scansPawley, G. S.Journal of Applied Crystallography (1981), 14 (6), 357-61CODEN: JACGAR; ISSN:0021-8898.A procedure for the refinement of the crystal unit cell from a powder diffraction scan is presented. Knowledge of the crystal structure is not required, and at the end of the refinement a list of indexed intensities is produced. This list may well be usable as the starting point for the application of direct methods. The problems of least-square ill-conditioning due to overlapping reflections are overcome by constraints. An example, using decafluorocyclohexene shows the quality of fit obtained in a case which may even be a false min. The method should become more relevant as powd. scans of improved resoln. become available, through the use of pulsed neutron sources.
- 70Rietveld, H. M. J. Appl. Crystallogr. 1969, 2, 65– 71 DOI: 10.1107/S002188986900655870https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1MXksVeisbk%253D&md5=3e3acdf00920ecd78a9bc042511e7fc4Profile refinement method for nuclear and magnetic structuresRietveld, H. M.Journal of Applied Crystallography (1969), 2 (Pt. 2), 65-71CODEN: JACGAR; ISSN:0021-8898.A structural refinement method for neutron diffraction is presented which makes direct use of the profile intensities obtained from the powder diagram. It is applicable to nuclear structures and to magnetic structures which can be described on the nuclear unit cell or a multiple thereof. Equations for the measured profiles to be used in the least sqs. treatment are cor. for asymmetry and preferred orientation; the angular dependence of the half widths of the peaks is given by the formula of Caglioti, et al. (1958). The magnetic contribution to the profile equation is expressed by calcg. only one av. cross section for each set of equiv. reflections. It is possible to introduce constraint functions, linear or quadratic, between parameters used in the least sqs. treatment. Results of the use of this method are given for a series of compds. In all instances it has proved superior to any other method involving integrated neutron powder intensities, single or overlapping.
- 71Coelho, A. A.TOPAS Academic V5; Coelho Software: Brisbane, Australia, 2012.There is no corresponding record for this reference.
- 72Ahlqvist, M. U. A.; Taylor, L. S. J. Pharm. Sci. 2002, 91, 690– 698 DOI: 10.1002/jps.10068There is no corresponding record for this reference.
- 73Braun, D. E.; Tocher, D. A.; Price, S. L.; Griesser, U. J. J. Phys. Chem. B 2012, 116, 3961– 3972 DOI: 10.1021/jp211948qThere is no corresponding record for this reference.
- 74Zencirci, N.; Gstrein, E.; Langes, C.; Griesser, U. J. Thermochim. Acta 2009, 485, 33– 42 DOI: 10.1016/j.tca.2008.12.00174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhvF2jtL8%253D&md5=f6f6990dc4414b2b02bc753adbe5161cTemperature- and moisture-dependent phase changes in crystal forms of barbituric acidZencirci, Neslihan; Gstrein, Elisabeth; Langes, Christoph; Griesser, Ulrich J.Thermochimica Acta (2009), 485 (1-2), 33-42CODEN: THACAS; ISSN:0040-6031. (Elsevier B.V.)The dihydrate of barbituric acid (BAc) and its dehydration product, form II were investigated by moisture sorption anal., hot-stage microscopy, differential scanning calorimetry, thermogravimetry, soln. calorimetry, IR- and Raman spectroscopy, as well as powder x-ray diffraction. The dihydrate desolvates already at and below 50% relative humidity (RH) at 25° whereas form II is stable ≤80% RH, where it transforms back to the dihydrate. The thermal dehydration of barbituric acid dihydrate (BAc-H2) is a single step, nucleation controlled process. The peritectic reaction of the hydrate was measured at 77° and a transformation enthalpy of ΔtrsHH2-II = 17.3 kJ mol-1 was calcd. for the interconversion between the hydrate and form II. An almost identical value of 17.0 kJ mol-1 was obtained from soln. calorimetry in water as solvent (ΔsolHH2 = 41.5, ΔsolHII = 24.5 kJ mol-1). Addnl. a high-temp. form (HT-form) of BAc, which is enantiotropically related to form II and unstable at ambient conditions was characterized. Furthermore, we obsd. that grinding of BAc with KBr induces a tautomeric change. Therefore, IR-spectra recorded with KBr-disks usually display a mixt. of tautomers, whereas the IR-spectra of the pure trioxo-form of BAc are obtained if alternative prepn. techniques are used.
- 75Braun, D. E.; Orlova, M.; Griesser, U. J. Cryst. Growth Des. 2014, 14, 4895– 4900 DOI: 10.1021/cg501159c75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFSqtbvJ&md5=33ca21837567f57b653af0ee554b5ac6Creatine: Polymorphs Predicted and FoundBraun, Doris E.; Orlova, Maria; Griesser, Ulrich J.Crystal Growth & Design (2014), 14 (10), 4895-4900CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)Hydrate and anhydrate crystal structure prediction (CSP) of creatine (CTN), a heavily used, poorly water-sol., zwitterionic compd., has enabled the finding and characterization of its anhydrate polymorphs, including the thermodn. room temp. form. Crystal structures of the novel forms were detd. by combining lab. powder X-ray diffraction data and ab initio generated structures. The computational method not only revealed all exptl. forms but also predicted the correct stability order, which was exptl. confirmed by measurements of the heat of hydration.
- 76Braun, D. E.; Oberacher, H.; Arnhard, K.; Orlova, M.; Griesser, U. J. CrystEngComm 2016, 18, 4053– 4067 DOI: 10.1039/C5CE01758KThere is no corresponding record for this reference.
- 77Riddick, J. A.; Bunger, W. B. Organic Solvents: Physical Properties and Methods of Purification, 4th ed.; Techniques of Chemistry; Wiley-Interscience: New York, 1986; Vol. 2.There is no corresponding record for this reference.
- 78
In DSC experiments of hydrates, performed with hermetically sealed pans, any water that is released from the hydrate will be kept in the system. An equilibrium water vapor pressure will build up in the small volume above the sample. Thus, the composition of the condensed phase will remain relatively constant.
There is no corresponding record for this reference. - 79Van der Spoel, D.; Van Maaren, P. J.; Larsson, P.; Timneanu, N. J. Phys. Chem. B 2006, 110, 4393– 4398 DOI: 10.1021/jp057253579https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFegtr4%253D&md5=520e1796834b151a6987d6405a38799cThermodynamics of Hydrogen Bonding in Hydrophilic and Hydrophobic MediaVan der Spoel, David; Van Maaren, Paul J.; Larsson, Per; Timneanu, NicusorJournal of Physical Chemistry B (2006), 110 (9), 4393-4398CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)The thermodn. of hydrogen bond breaking and formation was studied in aq. solns. of alc. (methanol, ethanol, 1-propanol) mols. An extensive series of over 400 mol. dynamics simulations with an aggregate length of over 900 ns was analyzed using an anal. technique in which hydrogen bond (HB) breaking is interpreted as an Eyring process, for which the Gibbs energy of activation ΔG⧧ can be detd. from the HB lifetime. By performing simulations at different temps., we were able to det. the enthalpy of activation ΔH⧧ and the entropy of activation TΔS⧧ for this process from the Van't Hoff relation. The equil. thermodn. was detd. sep., based on the no. of donor hydrogens that are involved in hydrogen bonds. Results (ΔH) are compared with exptl. data from Raman spectroscopy and found to be in good agreement for pure water and methanol. The ΔG as well as the ΔG⧧ are smooth functions of the compn. of the mixts. The main result of the calcns. is that ΔG is essentially independent of the environment (around 5 kJ/mol), suggesting that buried hydrogen bonds (e.g., in proteins) do not contribute significantly to protein stability. Enthalpically, HB formation is a downhill process in all substances; however, for the alcs. there is an entropic barrier of 6-7 kJ/mol, at 298.15 K, which cannot be detected in pure water.
- 80Markovitch, O.; Agmon, N. J. Phys. Chem. A 2007, 111, 2253– 2256 DOI: 10.1021/jp068960gThere is no corresponding record for this reference.
- 81Wendler, K.; Thar, J.; Zahn, S.; Kirchner, B. J. Phys. Chem. A 2010, 114, 9529– 9536 DOI: 10.1021/jp103470e81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVahsbjI&md5=6435e81c9715149cdaf7dd200f4cad11Estimating the Hydrogen Bond EnergyWendler, Katharina; Thar, Jens; Zahn, Stefan; Kirchner, BarbaraJournal of Physical Chemistry A (2010), 114 (35), 9529-9536CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)First, different approaches to detect hydrogen bonds and to evaluate their energies are introduced newly or are extended. Supermol. interaction energies of 256 dimers, each contg. one single hydrogen bond, were correlated to various descriptors by a fit function depending both on the donor and acceptor atoms of the hydrogen bond. On the one hand, descriptors were orbital-based parameters as the two-center or three-center shared electron no., products of ionization potentials and shared electron nos., and the natural bond orbital interaction energy. On the other hand, integral descriptors examd. were the acceptor-proton distance, the hydrogen bond angle, and the IR frequency shift of the donor-proton stretching vibration. Whereas an interaction energy dependence on 1/r3.8 was established, no correlation was found for the angle. Second, the fit functions are applied to hydrogen bonds in polypeptides, amino acid dimers, and water cluster, thus their reliability is demonstrated. Employing the fit functions to assign intramol. hydrogen bond energies in polypeptides, several side chain CH···O and CH···N hydrogen bonds were detected on the fly. Also, the fit functions describe rather well intermol. hydrogen bonds in amino acid dimers and the cooperativity of hydrogen bond energies in water clusters.
Supporting Information
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b01231.
Crystallographic information (list of CSD structures), determination of critical water activity (slurry method), temperature-dependent slurry experiments in water, variable relative humidity PXRD experiments, variable temperature spectroscopy, RH-perfusion isothermal calorimetry (PDF)
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