Analytical approaches to investigate salt disproportionation in tablet matrices by Raman spectroscopy and Raman mapping

Nie, Haichen; Liu, Zhen; Marks, Brian; Taylor, Lynne S.; Byrn, Stephen R.; Marsac, Patrick J.

doi:10.1016/j.jpba.2015.10.024

Cited by 44 publications

(55 citation statements)

References 34 publications

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“…Quantification of the crystallinity in the presence of its amorphous form or other components in a powder mixture has been reported (29–31). Under the assumption that experimentally measured crystalline and amorphous X-ray intensities or areas are proportional to the crystalline and amorphous fractions of the samples (32,33), the % crystallinity of Ciprofloxacin can be calculated by the following equation: % Crystallinity=AreacrystallineAreacrystalline+Areaamorphous×100%…”

Section: Methodsmentioning

confidence: 99%

Effects of Moisture-Induced Crystallization on the Aerosol Performance of Spray Dried Amorphous Ciprofloxacin Powder Formulations

et al. 2018

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Section: Methodsmentioning

confidence: 99%

Effects of Moisture-Induced Crystallization on the Aerosol Performance of Spray Dried Amorphous Ciprofloxacin Powder Formulations

et al. 2018

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“…However, it should be noted that such surface experimental element concentration could be underestimated as the X-ray penetration depth is approximately 1 μm and likely to penetrate into the particles. In addition, there is a possibility of salt disproportionation of Sulphur and Chlorine from the bases [44]. Therefore, more surface sensitive characterization techniques of XPS and ToF-SIMS were employed.…”

Section: Resultsmentioning

confidence: 99%

Improved Physical Stability and Aerosolization of Inhalable Amorphous Ciprofloxacin Powder Formulations by Incorporating Synergistic Colistin

et al. 2018

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This study aimed to develop dry powder inhaler (DPI) combination formulations of ciprofloxacin and colistin for use in respiratory infections. Effects of colistin on physical stability and aerosolization of spray-dried ciprofloxacin were examined. The combination DPI formulations were produced by co-spray drying colistin and ciprofloxacin in mass ratios of 1:1, 1:3, and 1:9. Colistin and ciprofloxacin were also co-sprayed with l-leucine in the mass ratio of 1:1:1. The physical and aerosolization stability of the selected co-sprayed formulations stored at 20, 55, and 75% relative humidity (RH) were examined. Formulation characterizations were carried out using powder X-ray diffraction (PXRD) for crystallinity, scanning electron microscopy for morphology and particle size distribution, and dynamic vapor sorption for moisture sorption. Particle surface analysis was performed using X-ray photoelectron spectroscopy, energy dispersive X-ray spectrometry, and nano-time-of-flight secondary ion mass spectrometry. Potential intermolecular interactions were studied using Fourier-transform infrared spectroscopy (FTIR). Aerosol performance was evaluated using a multistage liquid impinger with a RS01 monodose inhaler device. PXRD diffractograms showed that the co-spray-dried colistin-ciprofloxacin formulation in the mass ratio (1:1) was amorphous at 55% RH for up to 60 days; whereas the co-spray-dried colistin-ciprofloxacin (1:3) and colistin-ciprofloxacin (1:9) crystallized after storage for 3 days at 55% RH. However, the extent of crystallization for the combination formulations was less as compared to the spray-dried ciprofloxacin alone formulation. Surface morphology of the co-spray-dried formulations at different concentrations did not change even after storage at 55% RH for 60 days, unlike the spray-dried ciprofloxacin alone powder which became rougher after 3 days of storage at 55% RH. Surface analysis data indicated surface enrichment of colistin in the co-spray-dried formulations. Increasing colistin concentration on the composite particles surfaces improved aerosol performance of ciprofloxacin. FTIR data demonstrated intermolecular interactions between colistin and ciprofloxacin, thereby delaying and/or preventing crystallization of ciprofloxacin when co-spray-dried. Co-spray drying ciprofloxacin with colistin in the mass ratio (1:1) completely prevented crystallization of ciprofloxacin at 55% RH for up to 60 days. However, the colistin-ciprofloxacin formulation (1:1) began to fuse when stored at 75% RH due to moisture absorption resulting in a compromised aerosol performance. In contrast, the colistin-ciprofloxacin-leucine (1:1:1) formulation demonstrated no particle fusion, enabling a stable aerosol performance at 75% RH for 7 days. This study demonstrated that incorporation of colistin in the spray-dried formulations can improve physical stability and aerosolization of amorphous ciprofloxacin at 55% RH. At 75% RH, further addition of l-leucine in the formulation prevented particle fusion and deterioration in aeros...

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“…To validate that our SRS technique is capable of quantifying changes of chemical composition in a solid-state system, we first generated a PLS model within the spectral window of 1560–1760 cm –1 to test the capability of SRS to differentiate and quantify the amount of disproportionation. PLS is a multivariate regression method used to build quantitative calibration models and has been previously employed to study hyperspectral data of pharmaceutical formulations using NIR and Raman spectroscopy. ,− By mixing different ratios of PIO-HCl to PIO-FB, it is clear that the peak at 1610 cm –1 increases while the peak at 1640 cm –1 decreases as free base amount is increased, allowing us to directly discern the existence of PIO free base in the hsSRS data (Figure A). This spectral difference is attributed to a change in the vibrational modes of the pyridine ring and the carbonyl group after protonation …”

Section: Resultsmentioning

confidence: 99%

“…A variety of studies have been performed to investigate the roles of excipient chemistry, formulation storage, and stability to reveal influential factors in disproportionation. ,− One commonly used excipient is magnesium stearate (Mgst) which serves as a lubricant that reduces the adhesion between the powder and the processing equipment. However, Mgst is known to induce significant salt disproportionation of acidic APIs, especially at high relative humidity (RH). ,,− Recently, the HCl salt form of pioglitazone (PIO-HCl), which is used for treating type II diabetes, has become a popular model API for proof-of-concept methods to study disproportionation. ,,,, PIO-HCl has a tendency to readily undergo disproportionation to its free base (PIO-FB) due to its low disproportionation pH (pH max ) when interacting with problematic excipients. ,, Although previous studies have suggested that disproportionation is a solution-mediated transformation, the physical and chemical interplay between PIO-HCl, Mgst, and humidity is not well understood. Thus, to assist designs of robust formulations, it is critical to develop a complete mechanistic understanding of salt disproportionation.…”

mentioning

confidence: 99%

“…Label-free chemical imaging based on Raman spectroscopy can potentially address these limitations. Nie et al demonstrated that Raman spectroscopy could be used to study the disproportionation kinetics of PIO-HCL in a multicomponent tablet matrix at low quantities (5% drug loading) using a statistically optimized sampling method . Using the proposed approach, Raman imaging was successfully shown to detect disproportionation within the microenvironment of the API particle in tablet matrices with a lower detection limit than conventional Raman spectroscopy.…”

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confidence: 99%

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Detecting and Quantifying Microscale Chemical Reactions in Pharmaceutical Tablets by Stimulated Raman Scattering Microscopy

et al. 2019

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It has been estimated that approximately 50% of all marketed drug molecules are manufactured and administered in the form of salts, often with the goal of improving solubility, dissolution rate, and efficacy of the drug. However, salt disproportionation during processing or storage is a common adverse effect in these formulations. Due to the heterogeneous nature of solid drug formulations, it is essential to characterize the drug substances noninvasively at micrometer resolution to understand the molecular mechanism of salt disproportionation. However, there is a lack of such capability with current characterization methods. In this study, we demonstrate that stimulated Raman scattering (SRS) microscopy can be used to provide sensitive and quantitative chemical imaging of the salt disproportionation reaction of pioglitazone hydrochloride (PIO-HCl) at a very low drug loading (1% w/w). Our findings illuminate a water mediated pathway of drug disproportionation and highlight the importance of noninvasive chemical imaging in a mechanistic study of solid-state chemical reactions.

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Analytical approaches to investigate salt disproportionation in tablet matrices by Raman spectroscopy and Raman mapping

Cited by 44 publications

References 34 publications

Effects of Moisture-Induced Crystallization on the Aerosol Performance of Spray Dried Amorphous Ciprofloxacin Powder Formulations

Effects of Moisture-Induced Crystallization on the Aerosol Performance of Spray Dried Amorphous Ciprofloxacin Powder Formulations

Improved Physical Stability and Aerosolization of Inhalable Amorphous Ciprofloxacin Powder Formulations by Incorporating Synergistic Colistin

Detecting and Quantifying Microscale Chemical Reactions in Pharmaceutical Tablets by Stimulated Raman Scattering Microscopy

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