Structural, Thermodynamic, and Kinetic Aspectsof the Trimorphism of Hydrocortisone

Suitchmezian, Viktor; Jeß, Inke; Näther, Christian

doi:10.1002/jps.21334

Cited by 23 publications

(36 citation statements)

References 19 publications

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“…Together, these results could partly explain why the solubility levels of the fresh and spray-dried samples of these APIs were relatively higher than that of the unprocessed crystalline form. Even though hydrochlorothiazide, hydrocortisone, and sulfathiazole have been reported to have several different crystal forms [36,37,38], the exact crystal forms corresponding to the ones observed in our study could not be clearly identified.…”

Section: Resultscontrasting

confidence: 61%

Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage

et al. 2019

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This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (Cmax,app), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their Cmax,app and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its Cmax,app and AUC by 50%, with Cmax,app being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs.

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Section: Resultscontrasting

confidence: 61%

Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage

et al. 2019

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“…Section C; Linden (2011). Some recent publications of ours on the same theme include Hopf et al (2012), Jones et al (2011), Nä ther & Jess (2006, Suitchmezian et al (2008Suitchmezian et al ( , 2011.…”

Section: Introductionmentioning

confidence: 94%

Thermodynamic and structural relationships between the two polymorphs of 1,3-dimethylurea

Näther¹,

Döring²,

Jeß³

et al. 2012

Acta Crystallogr Sect B

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The title compound exists as polymorph (I), Fdd2 with Z = 8 [Pérez‐Folch et al. (1997). J. Chem. Cryst.27, 367–369; Marsh (2004). Acta Cryst. B60, 252–253], and as polymorph (II), P21212 with Z = 2 [Martins et al. (2009). J. Phys. Chem. A, 113, 5998–6003]. We have redetermined both structures at somewhat lower temperatures [(I) at 180 K rather than room temperature; (II) at 100 K rather than 150 K]. For polymorph (I) the space group Fdd2 is confirmed rather than the original choice of Cc. The molecular structures of both polymorphs are essentially identical, with exact crystallographic twofold symmetry, approximate C2v symmetry, and a trans orientation of the H—N—C=O moiety. In both polymorphs the molecules associate into chains of rings with graph set C(4)[R21(6)] via bifurcated hydrogen‐bond systems C(N—H)2...O=C. In the polar structure (I) the chains are necessarily all parallel, whereas in (II) equal numbers of parallel and antiparallel chains are present. Further physical investigations [differential scanning calorimetry (DSC), powder investigations, solvent‐induced phase conversions] were undertaken: these showed: (i) that the commercially available compound consists predominantly of polymorph (II), which on heating transforms into polymorph (I) by an endothermic reaction, so that both polymorphs are related by enantiotropism; (ii) that polymorph (I) represents the more stable modification at room temperature, where polymorph (II) is metastable, with the thermodynamic transition temperature lying somewhere between 253 K and room temperature. An apparent third polymorph, consisting of fibrous needles, was shown by powder diffraction to consist of a mixture of polymorphs (I) and (II).

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“…They crystallize in different structures and show different polymorphism. C has only one known polymorph in the P2 1 2 1 2 1 space group [CCDC (Groom et al, 2016) refcode DHPRTO; Declercq et al, 1972], while three polymorphs of HC are known: forms I (CCDC refcode ZZZPNG01) and III (CCDC refcode ZZZPNG03) in the P2 1 2 1 2 1 space group and form II (CCDC refcode ZZZPNG02) in the monoclinic P2 1 space group (Suitchmezian et al, 2008). No evident structural similarity is recognisable in these structures (Ká lmá n & Pá rká ny, 1997), phenomena that can be explained in terms of the different hydrogen-bond capabilities of the substituents, carbonyl and hydroxyl, on the C11.…”

Section: Single-crystal Analysismentioning

confidence: 99%

Cortisone and cortisol break hydrogen-bonding rules to make a drug–prodrug solid solution

Verma¹,

Bordignon²,

Chierotti³

et al. 2020

Int Union Crystallogr J

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Multidrug products enable more effective therapies and simpler administration regimens, provided that a stable formulation is prepared, with the desired composition. In this view, solid solutions have the advantage of combining the stability of a single crystalline phase with the potential of stoichiometry variation of a mixture. Here a drug–prodrug solid solution of cortisone and cortisol (hydrocortisone) is described. Despite the structural differences of the two components, the new phase is obtained both from solution and by supercritical CO2 assisted spray drying. In particular, to enter the solid solution, hydrocortisone must violate Etter's rules for hydrogen bonding. As a result, its dissolution rate is almost doubled.

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Structural, Thermodynamic, and Kinetic Aspectsof the Trimorphism of Hydrocortisone

Cited by 23 publications

References 19 publications

Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage

Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage

Thermodynamic and structural relationships between the two polymorphs of 1,3-dimethylurea

Cortisone and cortisol break hydrogen-bonding rules to make a drug–prodrug solid solution

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