Investigation of the Effects of Pharmaceutical Processing Upon Solid-State NMR Relaxation Times and Implications to Solid-State Formulation Stability

Lubach, Joseph W.; Xu, Dawei; Segmüller, Brigitte E.; Munson, Eric J.

doi:10.1002/jps.20684

Cited by 96 publications

(81 citation statements)

References 26 publications

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“…A similar trend was observed in work performed in our laboratory on lactose monohydrate cryoground for various lengths of time (9). Cryogrinding the as-received material for only 2 min reduced the 1 H T 1 value by more than 200 s. Lactose monohydrate cryoground for 60 min had a 1 H T 1 value two orders of magnitude shorter than the as-received material.…”

Section: Discussionsupporting

confidence: 85%

“…We have previously reported that grinding causes a decrease in 1 H T 1 times and stated that "relaxation measurements performed on dosage forms could potentially be used to predict stability of pharmaceutical formulations." (9) In this study, we show how SSNMR relaxation times were correlated to the propensity of the gabapentin to degrade to the lactam.…”

Section: Introductionmentioning

confidence: 84%

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Investigating Gabapentin Polymorphism Using Solid-State NMR Spectroscopy

et al. 2012

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Abstract. Solid-state NMR spectroscopy (SSNMR), coupled with powder X-ray diffraction (PXRD), was used to identify the physical forms of gabapentin in samples prepared by recrystallization, spray drying, dehydration, and milling. Four different crystalline forms of gabapentin were observed: form I, a monohydrate, form II, the most stable at ambient conditions, form III, produced by either recrystallization or milling, and an isomorphous desolvate produced from desolvating the monohydrate. As-received gabapentin (form II) was ball-milled for 45 min in both the presence and absence of hydroxypropylcellulose (HPC). The samples were then stored for 2 days at 50°C under 0% relative humidity and analyzed by 13 C SSNMR and PXRD. High-performance liquid chromatography was run on the samples to determine the amount of degradation product formed before and after storage. The 1 H T 1 values measured for the sample varied from 130 s for the as-received unstressed material without HPC to 11 s for the material that had been ball-milled in the presence of HPC. Samples with longer 1 H T 1 values were substantially more stable than samples that had shorter T 1 values. Samples milled with HPC had detectable form III crystals as well. These results suggest that SSNMR can be used to predict gabapentin stability in formulated products.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 84%

Investigating Gabapentin Polymorphism Using Solid-State NMR Spectroscopy

et al. 2012

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“…6) Furthermore, solid state proton relaxation time (T 1 ) studies can also provide useful information on molecular motion in the solid state. 7) Intrinsic dissolution test is a one of the attempt to measure the solubility of a metastable polymorph which can undergo a phase transformation to the more stable phase during dissolving procedure. In fact, equilibrium solubility may not be very relevant for study of polymorphs if polymorphs are physically unstable in the aqueous environment.…”

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confidence: 99%

Solid-State Carbon NMR Characterization and Investigation of Intrinsic Dissolution Behavior of Fluconazole Polymorphs, Anhydrate Forms I and II

Park

Kim

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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NotePolymorphism is defined as the occurrence of different crystalline forms of the same pure compound in which the molecules have different arrangement and/or conformation. 1)Many drugs are able to be crystallized in several polymorphic forms, each having a different energy and thereby differing in physicochemical and mechanical properties such as melting point, solubility, stability, heat of fusion, density, refractive index, compression behavior and hygroscopicity. 2)Supercritical fluid (SCF) based technologies are currently valid tools among various crystallization techniques to control the polymorphic form of pharmaceuticals.3) The differences of properties such as solubility may have implications for absorption of the active drug from its dosage form. These concerns have led to an increased regulatory interest in the solid-state properties. 4,5) Solid state NMR (SSNMR) spectroscopy is also an essential technique for the solid state characterization of pharmaceuticals. The SSNMR spectroscopy not only differentiates between polymorphic forms of a pharmaceutical, but also intimately probes the structural aspects of polymorphic form. 6) Furthermore, solid state proton relaxation time (T 1 ) studies can also provide useful information on molecular motion in the solid state. 7)Intrinsic dissolution test is a one of the attempt to measure the solubility of a metastable polymorph which can undergo a phase transformation to the more stable phase during dissolving procedure. In fact, equilibrium solubility may not be very relevant for study of polymorphs if polymorphs are physically unstable in the aqueous environment. Instead, intrinsic dissolution rate (IDR) and kinetic solubility may be more relevant parameters to consider while studying the oral absorption of polymorphs. 2,8,9) Fluconazole is designated chemically as 2,4-difluoroa,a 1 -bis(1H-1,2,4-triazol-L-ylmethyl) benzyl alcohol ( Fig. 1) and is the first of a new subclass of synthetic triazole antifungal agent.10) Three anhydrate polymorphic forms, one monohydrate and several solvates of fluconazole, have been prepared and characterized.11-20) However, there has been no published research involving the characterization of fluconazole polymorphs using SSNMR spectroscopy. Consequently, we investigate the characterization of two fluconazole polymorphs, anhydrate forms I and II prepared by the supercritical antisolvent (SAS) process using SSNMR spectroscopy to obtain the structural differences in molecular level between fluconazole polymorphs. General solid state characterization such as differential scanning calorimetry (DSC), Powder X-ray diffraction (PXRD), fourier transform infrared (FT-IR) and Raman spectroscopy were also performed. Furthermore, kinetic solubility and intrinsic dissolution tests in aqueous solution were performed to investigate the solubility profiles and dissolution properties of fluconazole polymorphs. ExperimentalMaterials Micronized fluconazole (99.0% purity) was kindly provided Hwail Pharm. Co., Ltd. (Korea). The CO 2 used was 99.9% p...

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“…This is indicative of a phase transition from a crystalline to an amorphous state. 29,30 After 60 min, of milling, evidence of crystallinity is absent from the 13 C SSNMR spectra with no observable change upon further milling. However, the proton relaxation data for both compounds shows, at short milling times, intermediary relaxation rates, which is demonstrative of material structurally distinct from, and in between, crystalline starting material and the ones milled for longer time periods.…”

Section: Resultsmentioning

confidence: 99%