Similar but Different: The Case of Metoprolol Tartrate and Succinate Salts

Paoli, Paola; Rossi, Patrizia; Macedi, Eleonora; Ienco, Andrea; Chelazzi, L.; Bartolucci, Gianluca; Bruni, B

doi:10.1021/acs.cgd.5b01383

Cited by 21 publications

(43 citation statements)

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“…The foregoing can be explained on the basis of the dependence of the solubility on pH for metoprolol succinate which decreases with increasing pH [43]. Such a decrease is attributed to the chemical structure of metoprolol succinate salt, which is made of the metoprolol cation and the dicarboxylate anion in a 2:1 ratio [44] with a pKa of 9.67 [45]. In this regard, this compound undergoes protonation in the acidic pH range, at the amine moiety, leading to enhanced drug solubility.…”

Section: Discussionmentioning

confidence: 99%

A Direct Compression Matrix Made from Xanthan Gum and Low Molecular Weight Chitosan Designed to Improve Compressibility in Controlled Release Tablets

et al. 2019

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The subject of our research is the optimization of direct compression (DC), controlled release drug matrices comprising chitosan/xanthan gum. The foregoing is considered from two main perspectives; the use of low molecular weight chitosan (LCS) with xanthan gum (XG) and the determination of important attributes for direct compression of the mixtures of the two polymers. Powder flow, deformation behaviour, and work of compression parameters were used to characterize powder and tableting properties. Compression pressure and LCS content within the matrix were investigated for their influence on the crushing strength of the tablets produced. Response surface methodology (RSM) was applied to determine the optimum parameters required for DC of the matrices investigated. Results confirm the positive contribution of LCS in enhancing powder compressibility and crushing strength of the resultant compacts. Compactibility of the XG/LCS mixtures was found to be more sensitive to applied compression pressure than LCS content. LCS can be added at concentrations as low as 15% w/w to achieve hard compacts, as indicated by the RSM results. The introduction of the plasticity factor, using LCS, to the fragmenting material XG was the main reason for the high volume reduction and reduced porosity of the polymer mixture. Combinations of XG with other commonly utilized polymers in controlled release studies such as glucosamine, hydroxypropyl methylcellulose (HPMC), Na alginate (ALG), guar gum, lactose and high molecular weight (HMW) chitosan were also used; all the foregoing polymers failed to reduce the matrix porosity beyond a certain compression pressure. Application of the LCS/XG mixture, at its optimum composition, for the controlled release of two model drugs (metoprolol succinate and dyphylline) was examined. The XG/LCS matrix at 15% w/w LCS content was found to control the release of metoprolol succinate and dyphylline. The former preparation confirmed the strong influence of compression pressure on changing the drug release profile. The latter preparation showed the ability of XG/LCS to extend the drug release at a fixed rate for 12 h of dissolution time after which the release became slightly slower.

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Section: Discussionmentioning

confidence: 99%

A Direct Compression Matrix Made from Xanthan Gum and Low Molecular Weight Chitosan Designed to Improve Compressibility in Controlled Release Tablets

et al. 2019

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“…The crystallization step plays an important role in the purification of intermediates and the final pharmaceutical ingredients [ 5 , 6 ]. The solubility of the target compound in different solvents [ 7 , 8 , 9 ] is required for the crystallization process.…”

Section: Introductionmentioning

confidence: 99%

Measurements, Thermodynamic Modeling, and a Hydrogen Bonding Study on the Solubilities of Metoprolol Succinate in Organic Solvents

Shen

Liang

2018

Molecules

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The solubilities of metoprolol succinate (a cardioselective β1 adrenergic receptor) in methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, and acetone were measured at temperatures ranging from (278.2 to 318.2) K using a solid–liquid equilibrium method. The solubility of metoprolol succinate increases with increasing temperature. At a fixed temperature, the solubility decreases in the order methanol > ethanol > n-butanol > n-propanol > isopropanol > acetone > ethyl acetate. The enthalpy of fusion and the melting point of metoprolol succinate were determined by differential scanning calorimetry. The thermodynamic properties of the dissolution process, determined by a van’t Hoff analysis, have been obtained and are discussed. The modified Apelblat equation, Wilson model, and non-random two-liquid (NRTL) model were employed to correlate the solubilities of metoprolol succinate in different solvents. Finally, a quantitative structure–property relationship (QSPR) study of physical properties of solvents and density functional theory simulations of hydrogen-bonding structure were carried out to give the explanation for the sequence of solubility in alcohols. The density functional theory (DFT) calculations well illustrated that the solubility of metoprolol succinate in various alcohols can be mainly attributed to the intra- and intermolecular hydrogen bonds in metoprolol succinate-solvent complexes.

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“…molecular conformations and crystal packing motifs), on their phase composition (fingerprinting and quantitative analysis), stability and transitions (e.g. solvation/desolvation processes; Rossi et al, 2014), polymorphic transformations (Paoli et al, 2016a) and lattice expansion/contraction (Paoli et al, 2016b), for example, upon temperature/pressure/atmosphere changes. Energies involved in phase transformations, together with the related temperatures, can be measured by DSC; in addition, DSC can be used to distinguish between enantiotropic and monotropic systems (Saunders & Gabbott, 2011).…”

Section: Introductionmentioning

confidence: 99%

A new crystal form of the NSAID dexketoprofen

Rossi

Paoli

Ienco³

et al. 2019

Acta Crystallogr C Struct Chem

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Dexketoprofen [(2S)‐2‐(3‐benzoylphenyl)propanoic acid], C16H14O3, is the S‐enantiomer of ketoprofen, a nonsteroidal anti‐inflammatory drug (NSAID) that has analgesic, antipyretic and anti‐inflammatory properties, and finds applications for the short‐term treatment of mild to moderate pain. A new crystalline phase of dexketoprofen is reported. Its solid‐state structure was determined by single‐crystal X‐ray diffraction (SCXRD). The molecular structure of the two independent molecules found in the asymmetric unit of this new phase (DXKP‐β) were compared to those of the already known crystal form of dexketoprofen (DXKP‐α) and with the S‐enantiomer of the racemic compound. The three different conformers of dexketoprofen found in DXKP‐α and DXKP‐β were then investigated by computational methods. The optimized structures are very close to the corresponding starting geometries and do not differ significantly in energy. The crystal packing of DXKP‐β was studied by means of Hirshfeld surface (HS) analysis; interaction energies were also calculated. A comparison with DXKP‐α shows close similarities between the two crystal forms, i.e. in both cases, molecules assemble through the catemer O—H…O synthon of the carboxylic acid stabilized by additional C—H…O contacts and, accordingly, the interaction energies, as well as the contributions to the HS area, are very similar. Finally, the thermal behaviour of the two polymorphs of dexketoprofen was assessed by means of XRD (both from single crystal and microcrystalline powder) and differential scanning calorimetry (DSC); both crystal forms are stable under the experimental conditions adopted (air, 300–350 K for DXKP‐α and 300–340 K DXKP‐β) and no solid–solid phase transition occurs between the two crystal forms in the investigated temperature range (from 100 K up to ca 350 K).

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Similar but Different: The Case of Metoprolol Tartrate and Succinate Salts

Abstract: The solid-state structure and behavior of tartrate (MT-o) and succinate (MS-m) metoprolol salts have been studied with a combined experimental (XRD by both single crystal and microcrystalline powder and DSC) and modeling approach (MD and MO calculations). In

Cited by 21 publications

References 54 publications

A Direct Compression Matrix Made from Xanthan Gum and Low Molecular Weight Chitosan Designed to Improve Compressibility in Controlled Release Tablets

A Direct Compression Matrix Made from Xanthan Gum and Low Molecular Weight Chitosan Designed to Improve Compressibility in Controlled Release Tablets

Measurements, Thermodynamic Modeling, and a Hydrogen Bonding Study on the Solubilities of Metoprolol Succinate in Organic Solvents

A new crystal form of the NSAID dexketoprofen

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