Solid-state NMR and IR for the analysis of pharmaceutical solids: Polymorphs of fosinopril sodium

Brittain, Harry G.; Morris, Kenneth R.; Bugay, David E.; Thakur, Ajit B.; Serajuddin, Abu T.M.

doi:10.1016/0731-7085(93)80083-d

Cited by 65 publications

(32 citation statements)

References 12 publications

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“…1 A study of polymorphs of this compound in the solid state demonstrated that the two conformers are formed and arise due to cis-trans isomerization around the amide bond. 4 Concentration-dependent behavior was observed in aqueous solution. 3 However, the conformers of fosinopril sodium in solution have not been reported.…”

Section: Introductionmentioning

confidence: 95%

Conformational study of fosinopril sodium in solution using NMR and molecular modeling

Liu

Shi

Zhang

et al. 2003

Magnetic Reson in Chemistry

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Two conformers of fosinopril sodium in methanol were unambiguously established using 2D NMR methods and variable-temperature NMR experiments. Differences in their conformational structure were shown to be related to the rotational energy barrier about the amide bond and hydrophobic interaction. The relationship between the 3D structure and activity is discussed. It is suggested that the trans-conformer may be more biologically active owing to its stacking structure and strong hydrophobic interaction and the cis-conformer could be more easily hydrolyzed because of its extended structure.

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Section: Introductionmentioning

confidence: 95%

Conformational study of fosinopril sodium in solution using NMR and molecular modeling

Liu

Shi

Zhang

et al. 2003

Magnetic Reson in Chemistry

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“…Particle size as well as degree of crystallinity can be profoundly affected by milling as has been observed in case of griseofulvin. 4 The use of a binder solution for wet granulation can cause solvent-mediated phase transformations, 5 and, finally, tablet compression has been reported to cause polymorphic conversions in hyoscine N-butyl bromide, piroxicam, caffeine, carbamazepine dihydrate, and chlorpropamide. 6 Drugs may also undergo multiple transformations during processing.…”

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confidence: 99%

Influence of processing-induced phase transformations on the dissolution of theophylline tablets

Debnath

Suryanarayanan

2004

AAPS PharmSciTech

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INTRODUCTIONThe object of this investigation was to evaluate the influence of (1) processing-induced decrease in drug crystallinity and (2) phase transformations during dissolution, on the performance of theophylline tablet formulations. Anhydrous theophylline underwent multiple transformations (anhydrate → hydrate → anhydrate) during processing. Although the crystallinity of the anhydrate obtained finally was lower than that of the unprocessed drug, it dissolved at a slower rate. This decrease in dissolution rate was attributed to the accelerated anhydrate to hydrate transformation during the dissolution run. Water vapor sorption studies proved to be a good predictor of powder dissolution behavior. While a decrease in crystallinity was brought about either by milling or by granulation, the effect on tablet dissolution was pronounced only in the latter. Tablet formulations prepared from the granules exhibited higher hardness, longer disintegration time, and slower dissolution than those containing the milled drug. The granules underwent plastic deformation during compression resulting in harder tablets, with delayed disintegration. The high hardness coupled with rapid anhydrate → hydrate transformation during dissolution resulted in the formation of a hydrate layer on the tablet surface, which further delayed tablet disintegration and, consequently, dissolution. Phase transformations during processing and, more importantly, during dissolution influenced the observed dissolution rates. Product performance was a complex function of the physical state of the active and the processing conditions.The physicochemical properties of pharmaceuticals, including solubility and dissolution rate, can be influenced by the degree of crystallinity, solvation state, and crystal form. At room temperature, the anhydrate forms of ampicillin, theophylline, and glutethimide have a higher dissolution rate than their corresponding hydrates. 1 This difference in dissolution rate can be attributed to the difference in the free energy of hydration.1 Similarly, metastable forms, because of their higher free energy, are expected to dissolve more rapidly than their corresponding stable forms. This effect was observed with the metastable polymorphs of acetazolamide, carbamazepine, and indomethacin.2 However, this free energy difference between the stable and metastable forms can also provide the driving force for metastable → stable transformation in the dissolution medium. As a result, the observed difference in dissolution rate can be much lower than the predicted values. 3Although the physical form of a drug substance is carefully selected for dosage form manufacture, the processing conditions will determine the solid state of the drug in the final product. During tablet manufacture, processing steps may include milling, granulation, drying, and compression. Particle size as well as degree of crystallinity can be profoundly affected by milling as has been observed in case of griseofulvin. 4 The use of a binder solution for wet gra...

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“…Solid-state NMR spectroscopy is now used extensively in pharmaceutical analysis, from polymorph identification all the way to final dosage form characterization [8][9][10][11][12][13][14][15]. It can characterize bulk drugs by identifying and quantitating polymorphs and mixtures of polymorphs (or hydrates/solvates), as well as mixtures of crystalline and amorphous forms.…”

Section: Introductionmentioning

confidence: 99%

Solid‐state NMR Spectroscopy

Lubach

Munson

2006

Polymorphism

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Solid-state NMR and IR for the analysis of pharmaceutical solids: Polymorphs of fosinopril sodium

Cited by 65 publications

References 12 publications

Conformational study of fosinopril sodium in solution using NMR and molecular modeling

Conformational study of fosinopril sodium in solution using NMR and molecular modeling

Influence of processing-induced phase transformations on the dissolution of theophylline tablets

Solid‐state NMR Spectroscopy

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