Physico-chemical characterization of an active pharmaceutical ingredient

Pfeffer-Hennig, S.; Piéchon, Philippe; Bellus, Miriam; Goldbronn, C.; Tedesco, Emilio

doi:10.1023/b:jtan.0000039002.79914.b7

Cited by 11 publications

(6 citation statements)

References 4 publications

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“…Its molecular mass is between 200 and 600 g/mol. Its physicochemical properties have been previously published . Carbamazepine form III was obtained from Novartis chemical production.…”

Section: Methodsmentioning

confidence: 99%

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Process Development Strategy to Ascertain Reproducible API Polymorph Manufacture

Müller

Meier

Wieckhusen

et al. 2006

Crystal Growth & Design

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The present example illustrates the application of a consistent process development strategy to ascertain reproducible active pharmaceutical ingredient (API) polymorph manufacture. Key methodologies are illustrated using a Novartis API and carbamazepine as model substances. In the present example, the Novartis API was synthesized in the final chemical step by hydrolysis followed by acidification. The process was investigated in four steps: First, solid-liquid equilibrium studies were carried out in several solvents and yielded two polymorphs that were characterized by X-ray powder diffraction. Reliable solubility data and the transition temperature (45 °C) were extracted from these experiments as well. Second, based on the knowledge of the enantiotropic behavior of the system, a procedure was developed that crystallized the stable polymorphswhich was chosen for developments reproducibly by seeding at low supersaturation below 45 °C, followed by cooling at a moderate rate. The absence of metastability with respect to the undesired polymorphic form throughout the process was confirmed by applying ATR-FTIR. Third, reaction conditions were modified to obtain the API in solution at undersaturated conditions. Subsequently, the API could be crystallized in a controlled manner as described above. Fourth, filtration, washing, and drying conditions were investigated to avoid scale-up problems. Constant pressure filtration yielded low compressibility of the filter cake allowing a nutsche or centrifuge as appropriate equipment for isolation. On the basis of vacuum thermogravimetry, fast drying kinetics could be determined. Bench scale paddle dryer experiments illustrated an unacceptable increase of bulk density at permanent rotation. Therefore, intermittent rotation was successfully used at production scale. Thus, the presented process development strategy leads to a robust process scale-up from lab to pilot and production plant, yielding the desired product quality with respect to physical properties as well as chemical purity. Using solid-liquid equilibrium studies, the solubility and the transition temperature (79 °C) between forms I and III of carbamazepine could be determined in 2-propanol. These results correspond well with findings of other authors. On the basis of vacuum thermogravimetry, fast drying kinetics of 2-propanol from carbamezepine is illustrated. Near-complete drying can be achieved at any pressure below the solvent vapor pressure, which points to solvent free from interactions with the solid drug substance.

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“…Its molecular mass is between 200 and 600 g/mol. Its physicochemical properties have been previously published . Carbamazepine form III was obtained from Novartis chemical production.…”

Section: Methodsmentioning

confidence: 99%

“…Its physicochemical properties have been previously published. 31 Carbamazepine form III was obtained from Novartis chemical production. Form I was prepared by heating form III at 140 °C for 4 h. 32 Ethanol quality abbreviated as EtOH (5% water) refers to plant grade quality containing 5% water and 6% 2-propanol.…”

Section: Methodsmentioning

confidence: 99%

Process Development Strategy to Ascertain Reproducible API Polymorph Manufacture

Müller

Meier

Wieckhusen

et al. 2006

Crystal Growth & Design

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“…In this paper, we have presented the reaction of nickel(II) nitrate with the dpyatriz ligand in acetonitrile, which yields tiny-crystals of [Ni 4 (dpyatriz) 2 (NO 3 ) 8 (CH 3 CN) 2 -(H 2 O) 2 ]‚2CH 3 CNformula (1), structurally characterized by X-ray diffraction using a synchrotron radiation source; 1 exhibits remarkable anion‚‚‚π interactions between the coordinated nitrate ions and the electron poor triazine rings. Amazingly, the compound is not stable in ambient conditions yet, through a number of solvent exchange and dehydration processes, it can be easily transformed into a number of pseudopolymorphic phases (2)(3)(4)(5), all containing a practically unchanged [Ni 4 (dpyatriz) 2 ] core.…”

Section: Discussionmentioning

confidence: 99%

“…Polymorphism is the ability of a solid material to exist in at least two different crystal packing arrangements. 1,2 Pseudopolymorphism defines the aptitude of a crystalline compound to form solvates or hydrates through the incorporation of respectively an organic solvent or water into the lattice of the solid-state structure. 3,4 The potential existence of various pseudopolymorphic forms for the same compound, associated with the consequent distinct physical properties, has been recognized and properly addressed, especially for pharmaceutical applications.…”

Section: Introductionmentioning

confidence: 99%

Rich Pseudopolymorphic Behavior of the Tetranuclear [Ni₄(dpyatriz)₂(NO₃)₈] Complex

et al. 2007

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Reaction of nickel(II) nitrate with the dpyatriz ligand, namely 2,4,6-tris(bis(pyridin-2-yl)amino)-1,3,5-triazine, in acetonitrile produces a tetranuclear NiII coordination compound, [Ni4(dpyatriz)2(NO3)8(CH3CN)2(H2O)2].2CH3CN (1), the crystal structure of which has been determined by X-ray diffraction using a synchrotron source. 1 has been characterized by IR and UV-vis spectroscopy, elemental and thermogravimetric analyses, and magnetic susceptibility measurements. Its solid-state structure exhibits remarkable anion...pi interactions between coordinated nitrate ions and the triazine rings. In addition, a thorough X-ray powder diffraction study has revealed a number of pseudopolymorphic phases (2-5), resulting from various degrees of hydration/solvation of the [Ni4(dpyatriz)2] core. The interconversion scheme among the different phases has been determined using controlled heating, and the basic structural features of the different pseudopolymorphs have been assessed through ab initio powder diffraction methods.

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“…Thermoanalytical methods (DSC/TG) are among the most important techniques to take physicochemical measurements and determine multiple structural forms and their phase transitions of a singular chemical entity [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. It has been shown earlier that DSC can reliably characterize the observed phase transition with <5 mg of a tripeptide sample [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Betulin-3,28-diphosphate. Physico-Chemical Properties and In Vitro Biological Activity Experiments

et al. 2018

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Betulin-3,28-diphosphate (BDP) obtained by phosphorylation of betulin using POCl3 has two main structural forms—BDP-1 and BDP-2—which differ in ethanol solubility, melting point, FTIR spectra, thermoanalytical characteristics and biological activity. Betulin-3,28-diphosphate and its sodium salt (Na-BDP) were characterized using 13C and 31P-NMR spectra, powder XRD experiments, as well as differential scanning calorimetry (DSC) and thermogravimetric analysis (TG) methods. The exo-effects at 193 ± 8 °C for ethanol soluble BDP-1 samples (−19.7 ± 0.2 kJ∙mol−1) were about three times less than for ethanol insoluble BDP-2 samples f (−70.5 ± 0.7 kJ∙mol−1). The DSC curves of Na-BDP-1 and Na-BDP-2 characterized the endo-effects having a maximum at 95–112 °C. Water-soluble Na-BDP-1 was obtained as needle-like crystals, unlike poorly crystalline Na-BDP-2, whereas BDP-1 and BDP-2 aged with time and were isolated as amorphous substances. In vitro experiments on rats showed that compared to the control, Na-BDP-1 increased catalase and SOD activity and improved energy metabolism more effectively than Na-BDP-2.

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Physico-chemical characterization of an active pharmaceutical ingredient

Cited by 11 publications

References 4 publications

Process Development Strategy to Ascertain Reproducible API Polymorph Manufacture

Process Development Strategy to Ascertain Reproducible API Polymorph Manufacture

Rich Pseudopolymorphic Behavior of the Tetranuclear [Ni₄(dpyatriz)₂(NO₃)₈] Complex

Betulin-3,28-diphosphate. Physico-Chemical Properties and In Vitro Biological Activity Experiments

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Physico-chemical characterization of an active pharmaceutical ingredient

Cited by 11 publications

References 4 publications

Process Development Strategy to Ascertain Reproducible API Polymorph Manufacture

Process Development Strategy to Ascertain Reproducible API Polymorph Manufacture

Rich Pseudopolymorphic Behavior of the Tetranuclear [Ni4(dpyatriz)2(NO3)8] Complex

Betulin-3,28-diphosphate. Physico-Chemical Properties and In Vitro Biological Activity Experiments

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Product

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Rich Pseudopolymorphic Behavior of the Tetranuclear [Ni₄(dpyatriz)₂(NO₃)₈] Complex