Zur Polymorphie von Dapson und Ethambutoldihydrochlorid

Kuhnert-Brandstätter, M.; Moser, Igo

doi:10.1007/bf01197529

Cited by 12 publications

(23 citation statements)

References 2 publications

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“…Thermal analysis and PXRD characterization confirmed that the new form V does not correspond to any of the four known polymorphs (Brandstaetter-Kuhnert et al, 1963 ; Kuhnert-Brandstatter and Moser, 1979 ). A thorough characterization of the new form, which is obviously the thermodynamically most stable anhydrate form at RT, and phase interrelations to the known polymorphs will be addressed elsewhere.…”

Section: Resultsmentioning

confidence: 86%

“…As such, it is listed in the WHO's List of Essential Medicines (medications satisfying the priority health care needs in humans) (World Health Organization, 2017 ). The compound is known to be polymorphic (anhydrate forms I – IV ), with form III being reported to be the most stable form (Brandstaetter-Kuhnert et al, 1963 ; Kuhnert-Brandstatter and Moser, 1979 ). Single crystal structures are known for anhydrate forms III (Dickinson et al, 1970 ; Deo et al, 1980 ; Bocelli and Cantoni, 1990 ; Su et al, 1992 ; Bertolasi et al, 1993 ) and II (Braun et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Supramolecular Organization of Nonstoichiometric Drug Hydrates: Dapsone

Braun

Griesser

2018

Front. Chem.

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The observed moisture- and temperature dependent transformations of the dapsone (4,4′-diaminodiphenyl sulfone, DDS) 0. 33-hydrate were correlated to its structure and the number and strength of the water-DDS intermolecular interactions. A combination of characterization techniques was used, including thermal analysis (hot-stage microscopy, differential scanning calorimetry and thermogravimetric analysis), gravimetric moisture sorption/desorption studies and variable humidity powder X-ray diffraction, along with computational modeling (crystal structure prediction and pair-wise intermolecular energy calculations). Depending on the relative humidity the hydrate contains between 0 and 0.33 molecules of water per molecule DDS. The crystal structure is retained upon dehydration indicating that DDS hydrate shows a non-stoichiometric (de)hydration behavior. Unexpectedly, the water molecules are not located in structural channels but at isolated-sites of the host framework, which is counterintuitively for a hydrate with non-stoichiometric behavior. The water-DDS interactions were estimated to be weaker than water-host interactions that are commonly observed in stoichiometric hydrates and the lattice energies of the isomorphic dehydration product (hydrate structure without water molecules) and (form III) differ only by ~1 kJ mol−1. The computational generation of hypothetical monohydrates confirms that the hydrate with the unusual DDS:water ratio of 3:1 is more stable than a feasible monohydrate structure. Overall, this study highlights that a deeper understanding of the formation of hydrates with non-stoichiometric behavior requires a multidisciplinary approach including suitable experimental and computational methods providing a firm basis for the development and manufacturing of high quality drug products.

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Section: Resultsmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Supramolecular Organization of Nonstoichiometric Drug Hydrates: Dapsone

Braun

Griesser

2018

Front. Chem.

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“…Hot-stage microscopy ( Figure 3) and differential scanning calorimetry ( Figure 4) were applied to reinvestigate the reported temperature induced transformations of Forms I-IV 29 and to complete the results with measurement data for form V and Hydehy. The thermochemical data are summarized in Table 1.…”

Section: Temperature Induced Phase Transformationsmentioning

confidence: 99%

“…The melting point of Form IV could be determined using faster heating rates in HSM investigations to be ~ 170 C, in agreement with a previous report. 29 For the remaining two polymorphs, Forms III and V, the melting points could not be determined.…”

Section: Thermodynamic Stability Of Dds Anhydrous Formsmentioning

confidence: 99%

“…The compound has been reported to be polymorphic (anhydrate forms I – IV ), with form III being mentioned to be the most stable anhydrous form. , A schematic diagram of the vapor pressure curves of the four modifications was constructed, indicating that the polymorphic pairs II / III , III / I , and I I/ I are enantiotropically related. The enantiotropic relationship between the isosymmetric polymorphs II and III was reinvestigated by us very recently, providing a molecular level understanding of the highly reversible transformation .…”

Section: Introductionmentioning

confidence: 99%

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Dapsone Form V: A Late Appearing Thermodynamic Polymorph of a Pharmaceutical

2019

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Five anhydrate polymorphs (Forms I-V) and the isomorphic dehydrate (Hydehy) of dapsone (4,4′diaminodiphenyl sulfone or DDS) were prepared and characterized in an interdisciplinary experimental and computational study, elucidating the kinetic and thermodynamic stabilities, solid form interrelationships and structural features of the known forms I-IV, the novel polymorph Form V, and Hydehy. Calorimetric measurements, solubility experiments and lattice energy calculations revealed that Form V is the thermodynamically stable polymorph from absolute zero to at least 90 C. At higher temperatures Form II and then Form I becomes the most stable DDS solid form. The computed 0 K stability order (lattice energy calculations) was confirmed with calorimetric measurements as follows: V (most stable) > III > Hydehy > II > I > IV (least stable). The discovery of Form V was complicated by the fact that the metastable but kinetically stabilized Form III shows a higher nucleation and growth rate. By combining laboratory powder X-ray diffraction data and ab initio calculations, the crystal structure of Form V (P21/c, Z′=4) was solved, with a high energy DDS conformation allowing a denser packing and more stable intermolecular interactions, rationalizing the formation of a high Z′ structure. The structures of the Forms I and IV, only observed from the melt and showing distinct packing features compared to the Forms II, III, and V, were derived from the computed crystal energy landscapes. Dehydration modelling of the DDS hydrate lead to the Hydehy structure. This study expands our understanding about the complex crystallization behavior of pharmaceuticals and highlights the big challenge in solid form screening, especially that there is no clear end point.

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Crystal and Molecular Structure of N,N′‐Bis(1‐hydroxy‐2‐butyl)ethylenediamine Dihydrochloride

Hämäläinen

Lehtinen

Ahlgrén

1985

Archiv der Pharmazie

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The structure of N,N'-bis( I-hydroxy-2-buty1)ethylenediamine dihydrochloride was determined by X-ray analysis. Die Kristall-und Molekularstruktur von N,N'-Bis(l-hydroxy-2-butyl)ethylendiamin-DihydrochloridDie Struktur von N,N'-Bis( 1-hydroxy-2-buty1)ethylendiamin-Dihydrochlorid wird durch Rontgenstrukturanalyse aufgeklart.Ethambutol dihydrochloride, (+)-N,N'-bis (l-hydroxy-2-butyl)-ethylenediamine dihydrochloride, is a chemotherapeutic agent widely used in medical treatment against Mycobacterium tuberculosis. The mode of action of the ethambutol at the molecular level is not known with certainty. Possibly it exerts its inhibitory effect on the growth of bacteria by interfering with a function of the cellular polyamines and divalent cations in RNA Ethambutol dihydrochloride can exist in many polymorphic modification^^^'. In addition to thermoanalytical and microscopical methods, X-ray powder diagrams have been used to study the appearance of these polymorphsS). Since the metal complex 036~-6233/115/0101-~0z6 $ 02 5010 8 VCH Verlagsgesellschaft rnbtl. Weinhem 1985

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Zur Polymorphie von Dapson und Ethambutoldihydrochlorid

Cited by 12 publications

References 2 publications

Supramolecular Organization of Nonstoichiometric Drug Hydrates: Dapsone

Supramolecular Organization of Nonstoichiometric Drug Hydrates: Dapsone

Dapsone Form V: A Late Appearing Thermodynamic Polymorph of a Pharmaceutical

Crystal and Molecular Structure of N,N′‐Bis(1‐hydroxy‐2‐butyl)ethylenediamine Dihydrochloride

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