Formation and Physicochemical Properties of Crystalline and Amorphous Salts with Different Stoichiometries Formed between Ciprofloxacin and Succinic Acid

Paluch, Krzysztof J.; McCabe, Thomas; Müller‐Bunz, Helge; Corrigan, Owen I.; Healy, Anne Marie; Tajber, Lidia

doi:10.1021/mp400127r

Cited by 75 publications

(86 citation statements)

References 51 publications

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“…Similar bands can be found in the FTIR spectra of CIP salts, in which the piperazine secondary amine is also ionized. 9,53 This peak appears to be absent from the sample spray dried …”

Section: Page 22 Of 42 Acs Paragon Plus Environmentmentioning

confidence: 99%

“…This is most likely due to the fact that it is not suitable for processing by the most common methods of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 amorphous solid generation. For example, CIP has been reported to decompose after melting, 9 which would rule out the use of melting techniques. In addition, due to its very low solubility in common solvents, solvent evaporation, spray drying and freeze drying are also quite unattractive options.…”

Section: Production Of Amorphous Ciprofloxacinmentioning

confidence: 99%

“…8 The solubility of CIP in water has been reported as 0.06 and 0.08 mg/mL at 25 o C and 37 o C respectively. 9 CIP is also poorly soluble in other common solvents such as ethanol, methanol, propanol, dichloromethane, acetone and chloroform. 10,11,12 The poor solubility of CIP may also be attributed to the strength of its crystal lattice, resulting in solid state-limited solubility.…”

Section: Introductionmentioning

confidence: 99%

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Two Faces of Ciprofloxacin: Investigation of Proton Transfer in Solid State Transformations

Mesallati

Mugheirbi

Tajber

2016

Crystal Growth & Design

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Ciprofloxacin (CIP) can exist in two different forms: the zwitterion and the unionized form. While the crystal structure of each has been described independently, the ability of CIP to transform from one to the other in the solid state has not been described. The crystal structures of unionized and zwitterionic CIP were therefore compared using computational methods, including their packing arrangement, hydrogen bonding, packing energy, intermolecular potentials and HOMO/LUMO energy gap. The pure amorphous form of CIP has also never been prepared or studied. Ball milling, cryomilling and spray drying were used in this study to prepare partially and fully amorphous CIP for the first time. The physical characteristics were examined by PXRD, FTIR and DSC. CIP proved to be very difficult to amorphize, and only spray drying in pure water resulted in a fully amorphous product. It was discovered that while most processing methods resulted in the more stable zwitterionic form of the drug, spray drying in an ethanol/water mixture produced the unionized form. The zwitterion was found to convert to the unionized form upon heating to its melting point, whereas the reverse transformation occurred when unionized CIP was exposed to high humidity. This study thus provides insight into the proton transfer which can occur in a zwitterionic drug in the solid state, and the resultant changes to its crystal structure. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 Abstract Ciprofloxacin (CIP) can exist in two different forms: the zwitterion and the unionized form.While the crystal structure of each has been described independently, the ability of CIP to transform from one to the other in the solid state has not been described. The crystal structures of unionized and zwitterionic CIP were therefore compared using computational methods, including their packing arrangement, hydrogen bonding, packing energy, intermolecular potentials and HOMO/LUMO energy gap. The pure amorphous form of this drug has also never been prepared or studied. Ball milling, cryomilling and spray drying were used in this study to prepare partially and fully amorphous CIP for the first time. The physical characteristics, and in particular ionization state, of these samples were examined by PXRD, FTIR and DSC. Analysis of the crystal packing of unionized and zwitterionic CIP revealed that the presence of ionic interactions between the charged groups of the latter results in a denser and more stable crystal lattice. A greater HOMO/LUMO energy gap was also calculated for this sample, confirming its lower reactivity. CIP proved to be very difficult to amo...

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“…Similar bands can be found in the FTIR spectra of CIP salts, in which the piperazine secondary amine is also ionized. 9,53 This peak appears to be absent from the sample spray dried …”

Section: Page 22 Of 42 Acs Paragon Plus Environmentmentioning

confidence: 99%

Section: Production Of Amorphous Ciprofloxacinmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Two Faces of Ciprofloxacin: Investigation of Proton Transfer in Solid State Transformations

Mesallati

Mugheirbi

Tajber

2016

Crystal Growth & Design

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“…This experimental protocol utilized an annealing step whereby physical mixtures of crystalline Td and PVP-VA were equilibrated at a chosen temperature above the Tg of the polymer and subsequently the melting point of the drug was determined applying a heating rate of 200 °C/min. It has been established that thermal decomposition of pharmaceutical substances can be minimized when using sufficiently fast heating rates [14].…”

Section: Introductionmentioning

confidence: 99%

Physical stability of solid dispersions with respect to thermodynamic solubility of tadalafil in PVP-VA

Wlodarski

Sawicki

Kozyra

et al. 2015

European Journal of Pharmaceutics and Biopharmaceutics

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The aim of this paper was to evaluate physical stability of solid dispersions in respect to the drug, tadalafil (Td), in vinylpyrrolidone and vinyl acetate block copolymer (PVP-VA). Nine solid dispersions of Td in PVP-VA (Td/PVP-VA) varied in terms of quantitative composition (1:9-9:1, w/w) were successfully produced by spray-drying. Their amorphous nature, supersaturated character and molecular level of mixing (a solid solution structure) were subsequently confirmed using DSC, PXRD, SEM and calculation of Hansen total solubility parameters. Due to thermal degradation of both components before the melting point of Td

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“…The PXRD patterns were recorded (n=3) from 5° to 40° on the 2 theta at a step scan rate of 0.05° per second (Paluch et al, 2013a).…”

Section: Physicochemical Characterisation Powder X-ray Diffraction (Pmentioning

confidence: 99%

Modelling and shadowgraph imaging of cocrystal dissolution and assessment of in vitro antimicrobial activity for sulfadimidine/4-aminosalicylic acid cocrystals

Serrano

Persoons

D’Arcy

et al. 2016

European Journal of Pharmaceutical Sciences

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Purpose: The aim of this work was to evaluate the influence of crystal habit on the dissolution and in vitro antibacterial and anitiprotozoal activity of sulfadimidine:4-aminosalicylic acid cocrystals.Methods: Cocrystals were produced via milling or solvent mediated processes. In vitro dissolution was carried out in the flow-through apparatus, with shadowgraph imaging and mechanistic mathematical models used to observe and simulate particle dissolution. In vitro activity was tested using agar diffusion assays.Results: Cocrystallisation via milling produced small polyhedral crystals with antimicrobial activity significantly higher than sulfadimidine alone, consistent with a fast dissolution rate which was matched only by cocrystals which were milled following solvent evaporation.Cocrystallisation by solvent evaporation (ethanol, acetone) or spray drying produced flattened, plate-like or quasi-spherical cocrystals, respectively, with more hydrophobic surfaces and greater tendency to form aggregates in aqueous media, limiting both the dissolution rate and in vitro activity. Deviation from predicted dissolution profiles was attributable to aggregation behaviour, supported by observations from shadowgraph imaging. Conclusions: Aggregation behaviour during dissolution of cocrystals with different habitsaffected the dissolution rate, consistent with in vitro activity. Combining mechanistic models with shadowgraph imaging is a valuable approach for dissolution process analysis.

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Formation and Physicochemical Properties of Crystalline and Amorphous Salts with Different Stoichiometries Formed between Ciprofloxacin and Succinic Acid

Cited by 75 publications

References 51 publications

Two Faces of Ciprofloxacin: Investigation of Proton Transfer in Solid State Transformations

Two Faces of Ciprofloxacin: Investigation of Proton Transfer in Solid State Transformations

Physical stability of solid dispersions with respect to thermodynamic solubility of tadalafil in PVP-VA

Modelling and shadowgraph imaging of cocrystal dissolution and assessment of in vitro antimicrobial activity for sulfadimidine/4-aminosalicylic acid cocrystals

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