Phase Diagrams of Polymer-Dispersed Liquid Crystal Systems of Itraconazole/Component Immiscibility Induced by Molecular Anisotropy.

Liquid crystalline (LC) materials and their nonmedical applications have been known for decades, especially in the production of displays; however, the pharmaceutical implications of the LC state are inadequately appreciated, and the misunderstanding of experimental data is leading to possible errors, especially in relation to the physical stability of medicines. The aim of this work was to study LC phases of itraconazole (ITZ), an azole antifungal active molecule, and for the first time, to generate full thermodynamic phase diagrams for ITZ/polymer systems, taking into account isotropic and anisotropic phases that this drug can form. It was found that supercooled ITZ does not form an amorphous but a vitrified smectic (vSm) phase with a glass transition temperature of 59.35 °C (determined using a 10 °C/min heating rate), as is evident from X-ray diffraction and thermomicroscopic (PLM) experiments. Two endothermic LC events with the onset temperature values for a smectic to nematic transition of 73.2 ± 0.4 °C and a nematic to isotropic transformation at 90.4 ± 0.35 °C and enthalpies of transition of 416 ± 34 J/mol and 842 ± 10 J/mol, respectively, were recorded. For the binary supercooled mixtures, PLM and differential scanning calorimetry showed a phase separation with birefringent vSm persistent over a wide polymer range, as noticed especially for the hypromellose acetate succinate (HAS) systems. Both, smectic and nematic, phases were detected for the supercooled ITZ/HAS and ITZ/methacrylic acid-ethyl acrylate copolymer (EUD) mixtures, while geometric restrictions inhibited the smectic formation in the ITZ/poly(acrylic acid) (CAR) systems. The Flory-Huggins lattice theory coupled with the Maier-Saupe-McMillan approach to model anisotropic ordering of molecules was successfully utilized to create phase diagrams for all ITZ/polymer mixtures. It was concluded that in a supercooled ITR/polymer mix, if ITZ is present in a LC phase, immiscibility as a result of molecule anisotropy is afforded. This study shows that the LC nature of ITZ cannot be disregarded when designing stable formulations containing this molecule.

Freeze drying of polyelectrolyte complex nanoparticles: Effect of nanoparticle composition and cryoprotectant selection.

This work investigates the impact of nanoparticle (NP) composition and effectiveness of cryo-/lyo-protectants in a freeze drying process, which was employed to convert liquid dispersions of polyelectrolyte complex (PEC) NPs into completely redispersible powders. PEC NPs, with and without peptide, were produced by complex coacervation. The cryo-/lyo-protectants investigated were mannitol, trehalose (TRE) and poly(ethylene glycol) (PEG). The solid state of lyophilised powders was studied by thermal analysis and X-ray diffraction. Cytotoxicity studies were done by MTS assay and flow cytometry. The presence of a cryoprotectant was essential to achieve a successful powder reconstitution. The concentration of TRE was optimised for each type of PEC NPs. Protamine- and hyaluronate-based NPs reconstituted better than chitosan- and chondroitin sulphate-based NPs, respectively. PEG polymers were found to be more effective cryoprotectants than TRE and best results were achieved using co-freeze drying of NPs with TRE and PEG. These ternary NPs/TRE/PEG samples were crystalline, with expected better storage stability. PEG polymers were well tolerated by Caco-2 cells, with the exception of linear PEG 10 kDa. This work shows that, as regards the formulation design and maximising NP loading in the dried product, optimisation of the cryoprotectant type and content is needed as it is highly dependent not only on the type of polyelectrolyte pair in the PEC, but also the polyions ratio.

Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin.

Ciprofloxacin (CIP) is a poorly soluble drug that also displays poor permeability. Attempts to improve the solubility of this drug to date have largely focused on the formation of crystalline salts and metal complexes. The aim of this study was to prepare amorphous solid dispersions (ASDs) by ball milling CIP with various polymers. Following examination of their solid state characteristics and physical stability, the solubility advantage of these ASDs was studied, and their permeability was investigated via parallel artificial membrane permeability assay (PAMPA). Finally, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the ASDs were compared to those of CIP. It was discovered that acidic polymers, such as Eudragit L100, Eudragit L100-55, Carbopol, and HPMCAS, were necessary for the amorphization of CIP. In each case, the positively charged secondary amine of CIP was found to interact with carboxylate groups in the polymers, forming amorphous polymeric drug salts. Although the ASDs began to crystallize within days under accelerated stability conditions, they remained fully X-ray amorphous following exposure to 90% RH at 25 °C, and demonstrated higher than predicted glass transition temperatures. The solubility of CIP in water and simulated intestinal fluid was also increased by all of the ASDs studied. Unlike a number of other solubility enhancing formulations, the ASDs did not decrease the permeability of the drug. Similarly, no decrease in antibiotic efficacy was observed, and significant improvements in the MIC and MBC of CIP were obtained with ASDs containing HPMCAS-LG and HPMCAS-MG. Therefore, ASDs may be a viable alternative for formulating CIP with improved solubility, bioavailability, and antimicrobial activity.

Cocrystal habit engineering to improve drug dissolution and alter derived powder properties.

OBJECTIVES: Cocrystallization of sulfadimidine (SDM) with suitable coformers, such as 4-aminosalicylic acid (4-ASA), combined with changes in the crystal habit can favourably alter its physicochemical properties. The aim of this work was to engineer SDM : 4-ASA cocrystals with different habits to investigate the effect on dissolution, and the derived powder properties of flow and compaction. METHODS: Cocrystals were prepared in a 1 : 1 molar ratio by solvent evaporation using ethanol (habit I) or acetone (habit II), solvent evaporation followed by grinding (habit III) and spray drying (habit IV). KEY FINDINGS: Powder X-ray diffraction showed Bragg peak position was the same in all the solid products. The peak intensity varied, indicating different preferred crystal orientation confirmed by SEM micrographs: large prismatic crystals (habit I), large plate-like crystals (habit II), small cube-like crystals (habit III) and microspheres (habit IV). The habit III exhibited the fasted dissolution rate; however, it underwent a polymorphic transition during dissolution. Habits I and IV exhibited the highest Carr's compressibility index, indicating poor flowability. However, habits II and III demonstrated improved flow. Spray drying resulted in cocrystals with improved compaction properties. CONCLUSIONS: Even for cocrystals with poor pharmaceutical characteristics, a habit can be engineered to alter the dissolution, flowability and compaction behaviour.

Self-assembled carrageenan/protamine polyelectrolyte nanoplexes-Investigation of critical parameters governing their formation and characteristics.

The aim of this work was to investigate the feasibility of cross-linker free polyelectrolyte complex formation at the nanoscale between carrageenan (CAR) and protamine (PROT). The properties of CAR/PROT nanoparticles (NPs) were dependent on the carrageenan type: kappa (KC), iota (IC) and lambda (LC), concentration of components, addition of divalent cations, weight mixing ratio (WMR) of constituents and mode of component addition. In the case of 0.1% w/v solutions, IC-based NPs had the smallest particle sizes (100-150nm) and low polydispersity indices (0.1-0.4). A decrease in the solution concentration from 0.1% to 0.05% w/v enabled the formation of KC/PROT NPs. All carrageenans exhibited the ability to form NPs with surface charge ranging from -190 to 40mV. The inclusion of divalent cations caused an increase in the particle size and zeta potential. Infrared analysis confirmed the presence of a complex between CAR and PROT and showed that IC chains undergo structural changes when forming NPs. Colloidal stability of NPs was related to the initial surface charge of particles and was time- and pH-dependent. IC was found to be the most suitable type of CAR when forming nanoplexes with PROT.

Molecular origin of enhanced proton conductivity in anhydrous ionic systems.

Ionic systems with enhanced proton conductivity are widely viewed as promising electrolytes in fuel cells and batteries. Nevertheless, a major challenge toward their commercial applications is determination of the factors controlling the fast proton hopping in anhydrous conditions. To address this issue, we have studied novel proton-conducting materials formed via a chemical reaction of lidocaine base with a series of acids characterized by a various number of proton-active sites. From ambient and high pressure experimental data, we have found that there are fundamental differences in the conducting properties of the examined salts. On the other hand, DFT calculations revealed that the internal proton hopping within the cation structure strongly affects the pathways of mobility of the charge carrier. These findings offer a fresh look on the Grotthuss-type mechanism in protic ionic glasses as well as provide new ideas for the design of anhydrous materials with exceptionally high proton conductivity.

Polymorphism in sulfadimidine/4-aminosalicylic acid cocrystals: solid-state characterization and physicochemical properties.

Polymorphism of crystalline drugs is a common phenomenon. However, the number of reported polymorphic cocrystals is very limited. In this work, the synthesis and solid-state characterization of a polymorphic cocrystal composed of sulfadimidine (SD) and 4-aminosalicylic acid (4-ASA) is reported for the first time. By liquid-assisted milling, the SD:4-ASA 1:1 form I cocrystal, the structure of which has been previously reported, was formed. By spray drying, a new polymorphic form (form II) of the SD:4-ASA 1:1 cocrystal was discovered which could also be obtained by solvent evaporation from ethanol and acetone. Structure determination of the form II cocrystal was calculated using high-resolution X-ray powder diffraction. The solubility of the SD:4-ASA 1:1 cocrystal was dependent on the pH and predicted by a model established for a two amphoteric component cocrystal. The form I cocrystal was found to be thermodynamically more stable in aqueous solution than form II, which showed transformation to form I. Dissolution studies revealed that the dissolution rate of SD from both cocrystals was enhanced when compared with a physical equimolar mixture and pure SD. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1385-1398, 2015.

Heat induced evaporative antisolvent nanoprecipitation (HIEAN) of itraconazole.

Itraconazole (ITR) is an antifungal drug with a limited bioavailability due to its poor aqueous solubility. In this study, ITR was used to investigate the impact of nanonisation and solid state change on drug's apparent solubility and dissolution. A bottom up approach to the production of amorphous ITR nanoparticles (NPs), composed of 100% drug, with a particle diameter below 250 nm, using heat induced evaporative antisolvent nanoprecipitation (HIEAN) from acetone was developed. The NPs demonstrated improved solubility and dissolution in simulated gastro-intestinal conditions when compared to amorphous ITR microparticles. The incorporation of polyethylene glycol (PEG) or its methoxylated derivative (MPEG) as a stabiliser enabled the production of smaller NPs with narrower particle size distribution and enhanced apparent solubility. MPEG stabilised NPs gave the greatest ITR supersaturation levels (up to 11.6±0.5 µg/ml) in simulated gastric fluids. The stabilising polymer was in an amorphous state. Dynamic vapour sorption data indicated no solid state changes in NP samples with water vapour at 25 °C, while crystallisation was apparent at 50 °C. HIEAN proved to be an efficient method of production of amorphous ITR NPs, with or without addition of a polymeric stabiliser, with enhanced pharmaceutical properties.

Observation of highly decoupled conductivity in protic ionic conductors.

Ionic liquids (ILs) are key materials for the development of a wide range of emerging technologies. Protic ionic liquids, an important class of ILs, have long been envisioned as promising anhydrous electrolytes for fuel cells. It is well known that in comparison to all other cations, protons exhibit abnormally high conductivity in water. Such superprotonic dynamics was expected in protic ionic conductors as well. However, many years of extensive studies led to the disappointing conclusion that this is not the case and most protic ionic liquids display subionic behavior. Therefore, the relatively low conductivity seems to be the main obstacle for the application of protic ionic liquids in fuel cells. Using dielectric spectroscopy, herein we report the observation of highly decoupled conductivity in a newly synthesized protic ionic conductor. We show that its proton transport is strongly decoupled from the structural relaxation, in terms of both temperature dependence and characteristic rates. This finding offers a fresh look on the charge transport mechanism in PILs and also provides new ideas for design of anhydrous materials with exceptionally high proton conductivity.

Dry powders for oral inhalation free of lactose carrier particles.

Dry powder inhaler (DPI) products have traditionally comprised a simple formulation of micronised drug mixed with a carrier excipient, typically lactose monohydrate. The presence of the carrier is aimed at overcoming issues of poor flowability and dispersibility, associated with the cohesive nature of small, micronised active pharmaceutical ingredient (API) particles. Both the powder blend and the DPI device must be carefully designed so as to ensure detachment of the micronised drug from the carrier excipient on inhalation. Over the last two decades there has been a significant body of research undertaken on the design of carrier-free formulations for DPI products. Many of these formulations are based on sophisticated particle engineering techniques; a common aim in formulation design of carrier-free products being to reduce the intrinsic cohesion of the particles, while maximising dispersion and delivery from the inhaler. In tandem with the development of alternative formulations has been the development of devices designed to ensure the efficient delivery and dispersion of carrier-free powder on inhalation. In this review we examine approaches to both the powder formulation and inhaler design for carrier-free DPI products.

Biopharmaceutical characterisation of ciprofloxacin-metallic ion interactions: comparative study into the effect of aluminium, calcium, zinc and iron on drug solubility and dissolution.

Ciprofloxacin bioavailability may be reduced when ciprofloxacin is co-administered with metallic ion containing preparations. In our previous study, physicochemical interaction between ciprofloxacin and ferrous sulphate was successfully simulated in vitro. In the present work, comparative in vitro ciprofloxacin solubility and dissolution studies were performed in the reactive media containing aluminium hydroxide, calcium carbonate or zinc sulphate. Solid phases collected from the dissolution vessel with aluminium hydroxide, calcium carbonate and zinc sulphate were investigated for their properties. The results obtained indicate that different types of adducts may form and retard ciprofloxacin solubility and dissolution. In the case of aluminium, no phase changes were observed. The solid phase generated in the presence of calcium carbonate was identified as hydrated ciprofloxacin base. Similarly to iron, a new complex consistent with Zn(SO4)2(Cl)2(ciprofloxacin)2 × nH2O stoichiometry was generated in the presence of relatively high concentrations of ciprofloxacin hydrochloride and zinc sulphate, indicating that small volume dissolution experiments can be useful for biorelevant dissolution tests.

Self-assembled hyaluronate/protamine polyelectrolyte nanoplexes: synthesis, stability, biocompatibility and potential use as peptide carriers.

This work investigates a new type of polyelectrolyte complex nanocarrier composed of hyaluronic acid (HA) and protamine (PROT). Small (approximately 60 nm) and negatively charged nanoparticles (NPs) with a polydispersity index of less than 0.2 were obtained with properties that were dependent on the mixing ratio, concentration of polyelectrolytes and molecular weight of HA. Salmon calcitonin (sCT) was efficiently (up to 100%) associated with the NPs, and the drug loading (9.6-39% w/w) was notably high, possibly due to an interaction between HA and sCT. The NPs released -70-80% of the sCT after 24 hours, with the estimated total amount of released sCT depending on the amount of HA and PROT present in the NPs. The isoelectric point of the NPs was close to pH 2, and the negative surface charge was maintained above this pH. The HA/PROT nanoplexes protected the sCT from enzymatic degradation and showed low toxicity to intestinal epithelial cells, and thus may be a promising oral delivery system for peptides.

Impact of alternative solid state forms and specific surface area of high-dose, hydrophilic active pharmaceutical ingredients on tabletability.

In order to investigate the effect of using different solid state forms and specific surface area (TBET) of active pharmaceutical ingredients on tabletability and dissolution performance, the mono- and dihydrated crystalline forms of chlorothiazide sodium and chlorothiazide potassium (CTZK) salts were compared to alternative anhydrous and amorphous forms, as well as to amorphous microparticles of chlorothiazide sodium and potassium which were produced by spray drying and had a large specific surface area. The tablet hardness and tensile strength, porosity, and specific surface area of single-component, convex tablets prepared at different compression pressures were characterized. Results confirmed the complexity of the compressibility mechanisms. In general it may be concluded that factors such as solid-state form (crystalline vs amorphous), type of hydration (presence of interstitial molecules of water, dehydrates), or specific surface area of the material have a direct impact on the tabletability of the powder. It was observed that, for powders of the same solid state form, those with a larger specific surface area compacted well, and better than powders of a lower surface area, even at relatively low compression pressures. Compacts prepared at lower compression pressures from high surface area porous microparticles presented the shortest times to dissolve, when compared with compacts made of equivalent materials, which had to be compressed at higher compression pressures in order to obtain satisfactory compacts. Therefore, materials composed of nanoparticulate microparticles (NPMPs) may be considered as suitable for direct compaction and possibly for inclusion in tablet formulations as bulking agents, APIs, carriers, or binders due to their good compactibility performance.

Formation and physicochemical properties of crystalline and amorphous salts with different stoichiometries formed between ciprofloxacin and succinic acid.

Multi-ionizable compounds, such as dicarboxylic acids, offer the possibility of forming salts of drugs with multiple stoichiometries. Attempts to crystallize ciprofloxacin, a poorly water-soluble, amphoteric molecule with succinic acid (S) resulted in isolation of ciprofloxacin hemisuccinate (1:1) trihydrate (CHS-I) and ciprofloxacin succinate (2:1) tetrahydrate (CS-I). Anhydrous ciprofloxacin hemisuccinate (CHS-II) and anhydrous ciprofloxacin succinate (CS-II) were also obtained. It was also possible to obtain stoichiometrically equivalent amorphous salt forms, CHS-III and CS-III, by spray drying and milling, respectively, of the drug and acid. Anhydrous CHS and CS had melting points at ∼215 and ∼228 °C, while the glass transition temperatures of CHS-III and CS-III were ∼101 and ∼79 °C, respectively. Dynamic solubility studies revealed the metastable nature of CS-I in aqueous media, resulting in a transformation of CS-I to a mix of CHS-I and ciprofloxacin 1:3.7 hydrate, consistent with the phase diagram. CS-III was observed to dissolve noncongruently leading to high and sustainable drug solution concentrations in water at 25 and 37 °C, with the ciprofloxacin concentration of 58.8±1.18 mg/mL after 1 h of the experiment at 37 °C. This work shows that crystalline salts with multiple stoichiometries and amorphous salts have diverse pharmaceutically relevant properties, including molecular, solid state, and solubility characteristics.

Steroid/mucokinetic hybrid nanoporous microparticles for pulmonary drug delivery.

In a number of pulmonary diseases, patients may develop abnormally viscous mucus reducing drug efficacy. To increase budesonide diffusion within lung fluid, we developed nanoporous microparticles (NPMPs) composed of budesonide and a mucokinetic, ambroxol hydrochloride, to be inhaled as a dry powder. Budesonide/ambroxol-HCl particles were formulated by spray drying and characterised by various physicochemicals methods. Aerodynamic properties were evaluated using a cascade impactor. Drugs apparent permeability coefficients were calculated across mucus producing Calu-3 cell monolayers cultivated at an air-liquid interface. Microparticles made only from budesonide and ambroxol-HCl had smooth surfaces. In the presence of ammonium carbonate ((NH4)2CO3), NPMPs were formulated, with significantly (P<0.05) superior aerodynamic properties (MMAD=1.87±0.22 µm and FPF=84.0±2.6%). The formation of nanopores and the increase in the specific surface area in the presence of (NH4)2CO3 were mainly attributed to the neutralisation of ambroxol-HCl to form ambroxol base. Thus, ambroxol base could behave in the same manner as budesonide and prompt nanoprecipitation when spray dried from an ethanol/water mix occurs. All formulations were amorphous, which should enhance dissolution rate and diffusion through lung fluid. These NPMPs were able to improve budesonide permeability across mucus producing Calu-3 cell monolayers (P<0.05) suggesting that they should be able to enhance budesonide diffusion in the lungs through viscous mucus.

Impact of process variables on the micromeritic and physicochemical properties of spray-dried porous microparticles, part I: introduction of a new morphology classification system.

OBJECTIVES: This work investigated the impact of spray drying variables such as feed concentration, solvent composition and the drying mode, on the micromeritic properties of chlorothiazide sodium (CTZNa) and chlorothiazide potassium (CTZK). METHODS: Microparticles were prepared by spray drying and characterised using thermal analysis, helium pycnometry, laser diffraction, specific surface area analysis and scanning electron microscopy. KEY FINDINGS: Microparticles produced under different process conditions presented several types of morphology. To systematise the description of morphology of microparticles, a novel morphology classification system was introduced. The shape of the microparticles was described as spherical (1) or irregular (2) and the surface was classified as smooth (A) or crumpled (B). Three classes of morphology of microparticles were discerned visually: class I, non-porous; classes II and III, comprising differing types of porosity characteristics. The interior was categorised as solid/continuous (α), hollow (ß), unknown (γ) and hollow with microparticulate content (δ). Nanoporous microparticles of CTZNa and CTZK, produced without recirculation of the drying gas, had the largest specific surface area of 72.3 and 90.2 m²/g, respectively, and presented morphology of class 1BIIIα. CONCLUSIONS: Alteration of spray drying process variables, particularly solvent composition and feed concentration can have a significant effect on the morphology of spray dried microparticulate products. Morphology of spray dried particles may be usefully described using the morphology classification system.

Impact of process variables on the micromeritic and physicochemical properties of spray-dried microparticles--Part II. Physicochemical characterisation of spray-dried materials.

OBJECTIVES: In this work we investigated the residual organic solvent content and physicochemical properties of spray-dried chlorothiazide sodium (CTZNa) and potassium (CTZK) salts. METHODS: The powders were characterised by thermal, X-ray diffraction, infrared and dynamic vapour sorption (DVS) analyses. Solvent levels were investigated by Karl-Fischer titration and gas chromatography. KEY FINDINGS: Spray-drying from water, methanol (MeOH) and mixes of MeOH and butyl acetate (BA) resulted in amorphous microparticles. The glass transition temperatures of CTZNa and CTZK were ∼192 and ∼159°C, respectively. These materials retained their amorphous nature when stored at 25°C in dry conditions for at least 6 months with no chemical decomposition observed. DVS determined the critical relative humidity of recrystallisation of CTZNa and CTZK to be 57% RH and 58% RH, respectively. The inlet temperature dependant oxidation of MeOH to formaldehyde was observed; the formaldehyde was seen to deposit within the amorphous matrix of spray-dried product. Spray-drying in the open blowing mode coupled with secondary drying resulted in a three-fold reduction in residual BA (below pharmacopoeial permitted daily exposure limit) compared to spray-drying in the closed mode. CONCLUSIONS: Experiments showed that recirculation of recovered drying gas increases the risk of deposition of residual solvents in the spray-dried product.

Exploring the assembly process and properties of novel crosslinker-free hyaluronate-based polyelectrolyte complex nanocarriers.

The aim of this work was to study the formulation of pharmaceutically relevant polyelectrolyte complex nanoparticles (NPs) composed of hyaluronic acid (HA) and chitosan (CS) containing no crosslinkers. The influence of polymer mixing ratio, concentration and molecular weight as well as the type of counterion in chitosan salt on properties of the resulting NPs was examined. Formulations and their components were studied by laser light scattering, viscosity, infrared spectroscopy and microscopy. Physical stability, isoelectric points and cytotoxicity of selected NPs were determined. By appropriate modification of HA molecular weight, stable and non-sedimenting NPs were successfully formed. Sonication was found to be an effective method to reduce the molecular weight of HA from 2882±25 to 176±4 kDa with no chemical changes in the HA structure observed. High molecular weight CS formed micron-sized entities at all compositions investigated. Positively and negatively charged NPs were obtained depending on the mixing ratio of the polymers, with CS glutamate NPs yielding more negatively charged particles compared to CS chloride NPs. The smallest NPs (149±11 nm) were formed using HA with molecular weight of 176 kDa. Cytotoxicity of NPs was dependent on environmental pH but HA was found to exert cytoprotective effects on Caco-2 cells.

A novel approach to crystallisation of nanodispersible microparticles by spray drying for improved tabletability.

High-dose API powders which are to be tableted by direct compression should have high compactibility and compressibility. This note reports on a novel approach to the manufacture of crystalline powders intended for direct compaction with improved compactibility and compressibility properties. The poorly compactable API, chlorothiazide, was spray dried from a water/acetone solvent mix producing additive-free nanocrystalline microparticles (NCMPs) of median particle size 3.5 µm. Tablets compacted from NCMPs had tensile strengths ranging from 0.5 to 4.6 MPa (compared to 0.6-0.9 MPa for tablets of micronised CTZ) at compression forces ranging from 6 kN to 13 kN. NCMP tablets also had high porosities (34-20%) and large specific surface areas (4.4-4.8m(2)/g). The time taken for tablets made of NCMPs to erode was not statistically longer (p>0.05) than for tablets made of micronised CTZ. Fragmentation of NCMPs on compression was observed. The volume fraction of particles below 1 µm present in the suspension recovered after erosion of NCMP tablets was 34.8±3.43%, while no nanosized particles were detected in the slurry after erosion of compacted micronised CTZ.

Biopharmaceutical characterization of ciprofloxacin HCl-ferrous sulfate interaction.

The ciprofloxacin-iron interaction, resulting in a lower bioavailability, is well documented in vivo; however, a mechanistic explanation supported by experimental data of this interaction is missing. In the present study, ciprofloxacin hydrochloride (HCl) and ferrous sulfate interaction was simulated in vitro by performing solubility and dissolution studies in the reactive media containing ferrous sulfate. Characterization of the precipitate formed indicated its probable chemical structure as Fe(SO(4) (2-) )(2) (Cl(-) )(2) (ciprofloxacin)(2) × (H(2) O)(n) , where n is up to 12 molecules of water. The solubility of this complex in water was estimated to be approximately 2 mg/mL, being about 20-fold lower than the solubility of ciprofloxacin HCl. The solubility of the complex was used as input parameter for an in silico modeling by GastroPlus™ and the resulting predicted plasma time curves were in good agreement with the in vivo data. These results strongly indicate that ciprofloxacin-iron interaction in vivo is caused by the formation of a low soluble complex. This interaction was also simulated by in vitro dissolution, in which a mini scale apparatus provided more biorelevant results than the standard dissolution apparatus, probably because the drug concentrations in the mini apparatus were higher and, thus, closer to the conditions encountered in vivo.