Disproportionation of the calcium salt of atorvastatin in the presence of acidic excipients

Christensen, Niels Peter Aae; Rantanen, Jukka; Cornett, Claus; Taylor, Lynne S.

doi:10.1016/j.ejpb.2012.07.003

Cited by 34 publications

(24 citation statements)

References 24 publications

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“…Furthermore, the dissolution of FZP/Na is not significantly improved in the gastric pH condition. There are also some general concerns on salt drugs such as dissociation of base or acid drug and its counter ion, transition of crystallinity during manufacturing and storage (Christensen et al., 2012; Guerrieri & Taylor, 2009; Stephenson et al., 2011). As these properties have a marked impact on the physicochemical properties of drugs, salt formation approach is sometimes unsuitable for improvement of dissolution behavior.…”

Section: Introductionmentioning

confidence: 99%

Nanocrystal solid dispersion of fuzapladib free acid with improved oral bioavailability

Yamada

Hayashi

Sasaki

et al. 2022

Biopharm & Drug Disp

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This study aimed to develop an oral nanocrystal solid dispersion (nCSD) of fuzapladib (FZP) with enhanced absorbability for the treatment of acute pancreatitis (AP). The hydration properties of crystalline FZP free acid (crystalline FZP) and FZP sodium salt (FZP/Na) were assessed to select a stable crystal form. The nCSD of FZP free acid (nCSD/FZP) was prepared using a multi-inlet vortex mixer and evaluated in terms of physicochemical and pharmacokinetic properties. The results of X-ray powder diffraction analysis indicated that crystalline FZP was stable as an anhydrate, while FZP/Na was converted to its monohydrate at water activity of above 0.2. The nanocrystals in nCSD/FZP were dispersed in hydroxy propyl cellulose-SSL, and their mean particle size were 160 nm with uniform spherical shape. In dissolution testing, nCSD/FZP exhibited rapid dissolution compared with crystalline FZP and reached a saturated concentration of FZP within initial 30 min.After oral administration (2 mg-FZP/kg) to rats, the maximum plasma concentration and bioavailability were 7.3-and 5.2-fold higher for nCSD/FZP than crystalline FZP, respectively, due to improved dissolution by nanosization. In conclusion, nCSD/FZP may be a novel oral dosage form with enhanced absorbability facilitating potent therapeutic effects of FZP for the treatment of AP in animals. K E Y W O R D Sfuzapladib, hydration property, multi-inlet vortex mixer, nanocrystal solid dispersion, oral bioavailability | INTRODUCTIONFuzapladib (FZP) prevents inflammatory cells from entering inflammatory sites by inhibiting cell adhesion to the vascular endothelial cells (Imamura et al., 2003;Shikama et al., 1999;Yamauchi et al., 1999;Yotsuya et al., 1999), and it was recently approved as a novel drug for the treatment of acute pancreatitis (AP) in dogs.Despite its attractive therapeutic effects against AP, BRENDA TM , a commercially available formulation of FZP, shows rapid elimination after intravenous administration, possibly resulting in limited clinical outcomes with only a single dose. Therefore, the dose frequency of BRENDA TM to dogs is set as once daily for 5 days to ensure therapeutic effects against AP. The commercial formulation of FZP has another limitation for clinical use. There are some concerns regarding the chemical and physical stability of FZP in solution, so it is necessary to dissolve freeze-dried powder just before use. There are clinical needs for a solid formulation of FZP with ease of administration. FZP free acid (SH-683) itself is a poorly water-soluble compound with pK a of 5.1 (Figure S1), so it shows pH-dependent solubility: 20 μg/ml in pH 1-4, 27 μg/ml in pH 5, 65 μg/ml in pH 6, and 280 μg/ml in pH 7 (Figure S2). Therefore, dissolution behavior should be improved when developing a solid formulation of FZP.

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Section: Introductionmentioning

confidence: 99%

Nanocrystal solid dispersion of fuzapladib free acid with improved oral bioavailability

Yamada

Hayashi

Sasaki

et al. 2022

Biopharm & Drug Disp

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“…An estimated 50–70% of all developed small molecule drugs are administered as salts. , However, the success of using these ionized species in tablets significantly depends on their stability both before and during drug release, , as there is a tendency for the salt to convert back to its free (unionized) form under certain conditions via a reaction known as salt disproportionation. , Salt disproportionation is an acid–base reaction involving a proton exchange in the presence of water. − The conversion of the salt to the free form is undesirable since it may have detrimental effects on solid-state properties and pharmaceutical product performance, such as reduced dissolution rate and bioavailability. ,,− …”

Section: Introductionmentioning

confidence: 99%

“…The microenvironmental pH is another important factor that can influence salt disproportionation in both the solid state and solution phase. It refers to the hydrogen ion activity (i.e., pH) in the microscopic layer of water around the solid surface. ,, In the case of solid-dosage forms, the microenvironmental pH may be significantly impacted by the excipients possessing acidic or basic functionalities that are in intimate contact with the salt drug in multicomponent formulations. As a result, the salt propensity to disproportionate can be anticipated based on an assessment of the microenvironmental pH and knowledge of the salt pH max .…”

Section: Introductionmentioning

confidence: 99%

Effect of Excipients on Salt Disproportionation during Dissolution: A Novel Application of In Situ Raman Imaging

et al. 2021

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We have employed a bespoke setup combining confocal Raman microscopy and an ultraviolet–visible (UV–Vis) spectroscopy flow cell to investigate the effect of excipients on the disproportionation kinetics of Pioglitazone HCl (PioHCl) in tablets during dissolution. Three binary formulations of PioHCl, containing citric acid monohydrate (CA), lactose monohydrate (LM), or magnesium stearate (MgSt), respectively, were used as models to study the influence of excipients’ physicochemical properties on the rate of salt disproportionation kinetics and dissolution performance in different aqueous pH environments. It was found that formulation excipients can induce or prevent salt disproportionation by modulating the microenvironmental pH regardless of the pH of the dissolution media. Incorporating CA in PioHCl tablets preserves the salt form and enhances the dissolution performance of the salt in the acidic medium (pH = 1.2). In contrast, LM and MgSt had a detrimental effect on in vitro drug performance by inducing salt disproportionation in the tablet during dissolution in the same acidic medium. Dissolution in the neutral medium (pH = 6.8) showed rapid formation of the free base upon contact with the dissolution medium. The Raman maps of the cross-sectioned tablets revealed the formation of a shell consisting of the free base around the edge of the tablet. This shell decreased the rate of penetration of the dissolution medium into the tablet, which had significant implications on the release of the API into the surrounding solution, as shown by the UV–vis absorption spectroscopy drug release data. Our findings highlight the utility of the Raman/UV–vis flow cell analytical platform as an advanced analytical technique to investigate the effect of excipients and dissolution media on salt disproportionation in real time. This methodology will be used to enhance our understanding of salt stability studies that may pave the way for more stable multicomponent formulations.

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“…Although the concept of pH does not typically apply to solids, the local pH refers to the pH in a microscopic layer of adsorbed water at a solid surface in which the surface molecules are mobilized. ,, In the case of solid dosage forms, the local pH can be greatly influenced by excipients possessing acid/base functionalities that are in intimate contact in a multicomponent formulation. 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.…”

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confidence: 99%

“…Various analytical techniques have been used to study salt disproportionation of PIO-HCl. [4][5][6]15,16,19,21,22,26 Hirsh et al used 35 Cl solid-state NMR (ssNMR) to characterize the disproportionation reaction of PIO-HCl in mixtures with metallic stearates. 22 By directly probing the Cl − anions in both the intact salt and disproportionation products, the ssNMR spectra provided proof of the reactions between the chloride anions in the API salt and the metal cations in the stearates to produce solid salts such as NaCl or MgCl 2 .…”

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confidence: 99%

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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Disproportionation of the calcium salt of atorvastatin in the presence of acidic excipients

Cited by 34 publications

References 24 publications

Nanocrystal solid dispersion of fuzapladib free acid with improved oral bioavailability

Nanocrystal solid dispersion of fuzapladib free acid with improved oral bioavailability

Effect of Excipients on Salt Disproportionation during Dissolution: A Novel Application of In Situ Raman Imaging

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

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