Marcela R. Longhi

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Furosemide

Literature and new experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing furosemide are reviewed. The available data on solubility, oral absorption, and permeability are sufficiently conclusive to classify furosemide into Class IV of the Biopharmaceutics Classification System (BCS). Furosemides therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. In view of the data available, it is concluded that the biowaiver procedure cannot be justified for either the registration of new multisource drug products or major postapproval changes (variations) to existing drug products.

An efficient ternary complex of acetazolamide with HP-ß-CD and TEA for topical ocular administration

In order to enhance the ocular bioavailability of acetazolamide (ACZ), a multicomponent complex with hydroxypropyl-ss-cyclodextrin (HP-ss-CD) and triethanolamine (TEA) was prepared to be applied topically. In vitro corneal permeation across isolated rabbit cornea of proposed ACZ formulations and the marketed AZOPT(R) formulation (1% w/v brinzolamide) was studied. Formulations were also tested for their effect on the intraocular pressure (IOP) in rabbits. (1)H- and (13)C-NMR experiments were undertaken to verify the real inclusion of ACZ in the ACZ-HP-ss-CD-TEA multicomponent complex. The binding of ACZ to HP-ss-CD in the presence of TEA is described. The increase of TEA concentration decreases the apparent equilibrium constant for the ACZ-HP-ss-CD complex. The ternary system ACZ-HP-ss-CD-TEA seemed to be able to reduce IOP in about 30%. This effect was sustained for 4 h after instillation. In vitro corneal permeation studies demonstrated that the ACZ permeation was increased. RMN experiments indicated that TEA can weaken the association between ACZ and HP-ss-CD increasing the drug ocular hypotensive effect by increasing the free drug available for absorption. Our formulations were considered practically non-irritant. These results indicate that the ternary system ACZ-HP-ss-CD-TEA might be a useful tool for formulating aqueous ACZ eye drop solutions.

Biowaiver monographs for immediate release solid oral dosage forms: Acetazolamide

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing acetazolamide are reviewed. Acetazolamides solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are taken into consideration. The available data on solubility, on oral absorption and permeability are not sufficiently conclusive to classify acetazolamide with certainty. Taking a conservative approach, no biowaiver is considered justified for the registration of new multisource drug products. However, SUPAC level 1 and level 2 postapproval changes and most EU Type I variations can be approved waiving in vivo BE studies.

Studies on trimethoprim:hydroxypropyl-β-cyclodextrin: aggregate and complex formation

The present study is focused on the characterization of the interaction between trimethoprim, a dihydropteroate synthesase inhibitor, and hydroxypropyl-β-cyclodextrin (HP-β-CD) in aqueous solution and solid state. The freeze-drying method was used to prepare solid complexes, while simple blending was employed to obtain physical mixtures. The phase solubility was AN type, and demonstrated that trimethoprim solubility was significantly increased upon complexation with HP-β-CD. Conductivity experiments showed the presence of aggregates that explains the type profile for the solubility isotherm. The critical concentration for the aggregate formation was determined to be 69.3mg/ml for pure HP-β-CD and 117.7 mg/ml in the presence of trimethoprim. Nuclear magnetic resonance spectroscopy provided evidence of trimethoprim:HP-β-CD molecular interaction in solution. Moreover, the complex was characterized in solid stated using Fourier-transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). The use of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) showed that the thermal stability of the drug is enhanced in the presence of HP-β-CD.

Sulfamethoxazole:hydroxypropyl-β-cyclodextrin complex: preparation and characterization

A complex of sulfamethoxazole (SMX) and hydroxypropyl-β-cyclodextrin (HP-β-CD) was developed and characterized in order to investigate their interactions in aqueous solution and the solid state. The SMX solubility was significantly increased upon complexation with HP-β-CD, with the solubility isotherm being an A(N) type due to the presence of aggregates and the stability constant calculated for a 1:1 complex being 302 ± 3 M⁻¹. Fourier-transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM) experiments were used to compare the freeze-dried system with a physical mixture, and demonstrated the complex formation in the solid state. The differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) showed that the thermal stability of SMX was enhanced in the presence of HP-β-CD.

Development of HPLC and UV spectrophotometric methods for the determination of ascorbic acid using hydroxypropyl-β-cyclodextrin and triethanolamine as photostabilizing agents

In this study, the effect of complex formation with triethanolamine (TEA) alone and in combination with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on the photostability of ascorbic acid was evaluated for exposure to artificial and diffuse daylight. The first-order rate constants for the photodegradation reactions were determined. The data obtained showed that these complexes strongly reduced the photodegradation process with an 11- and 35-fold increase in the photostability of ascorbic acid, depending of the ligand concentration and the irradiation source. The multicomponent complex gave a significantly better stabilization for exposure to light than TEA alone. Due to the fact that the complexation extended the exposure of ascorbic acid to light (without molecular changes), UV spectrophotometric and reversed phase high performance liquid chromatographic (HPLC) methods were developed for the quantitative determination of the vitamin in pure form and in pharmaceutical preparations. These methods were statistically validated, all the validation parameters were found to be within the acceptance range. These results demonstrate that the proposed methods are suitable for the quality control of ascorbic acid, providing simple, rapid, precise, accurate and convenient approaches for routine analysis of bulk drug and pharmaceutical formulations.

Solubilization of naphthoquinones by complexation with hydroxypropyl-β-cyclodextrin

Abstract The effects of the hydroxypropyl- β -cyclodextrin (HPCD) on the solubility of 2-hydroxy- N -(5-methyl-3-isoxazolyl)-1,4-naphthoquinone-4-imine ( I ) were investigated. I is an experimental drug for the treatment of cancer which exhibits low water solubility and it is therefore difficult to prepare the solutions for biological tests. The presence of an ionizable hydroxyl moiety (p K a =5.80) increases the solubility via pH adjustment, but only a solubility of 0.124 mg/ml was obtained at pH 8.00. I was found to form inclusion complexes in either its neutral or its anionic form with HPCD. Although the stability constant of the I complex is larger in the neutral form, a greater overall solubility is obtained when I is in its ionized form. A 270-fold solubility enhancement is possible by using a combined approach of pH adjustment and complexation with HPCD.

Inclusion complexes of chloramphenicol with β-cyclodextrin and aminoacids as a way to increase drug solubility and modulate ROS production

The aim of this study was to improve the solubility of chloramphenicol and reduce the production of reactive oxygen species (ROS) in leucocytes induced by this drug, using complexation. Multicomponent complexes were prepared by the addition of β-cyclodextrin with glycine or cysteine. Nuclear magnetic resonance and phase solubility studies provided information at the molecular level on the structure of the complexes and their association binding constants, respectively. In the solid state, all systems were extensively characterized by Fourier-transform infrared spectroscopy, scanning electron microscopy, thermal analysis and X-ray powder diffraction. Antimicrobial activity of inclusion complexes was investigated by agar diffusion methods. Finally ROS determination by chemiluminescence was used to investigate the effect of complex formation on the potential toxicity in human leucocytes. These studies revealed that multicomponent complexes can increase the aqueous solubility of chloramphenicol as well as reducing the stress by ROS production in leucocytes and maintaining its microbiological activity.

Second derivative spectrophotometric determination of trimethoprime and sulfamethoxazole in the presence of hydroxypropyl-β-cyclodextrin (HP-β-CD)

Abstract An easy and rapid second-derivative spectrophotometric method for the simultaneous analysis of trimethoprime (TMP) and sulfamethoxazole (SM) is described. These drugs have been used as antibacterial against a wide spectrum of organisms and combinations of these drugs are commonly used for the treatment of a variety of infections. The most advantageous approach of this method is the use of HP-β-CD, which allows to improve the performance of the second-derivative ultraviolet spectrophotometry. For both compounds, a shift of the absorption bands and variations of their intensity were observed. The calibration graphs were linear in the concentration range of TMP (1.92–19.2 μg ml −1 ) and SM (1.60–16.5 μg ml −1 ), the correlation coefficient for the calibration graphs was better than 0.9994 and the precision was satisfactory (CV%

Investigating Albendazole Desmotropes by Solid-State NMR Spectroscopy

Characterization of the molecular structure and physicochemical solid-state properties of the solid forms of pharmaceutical compounds is a key requirement for successful commercialization as potential active ingredients in drug products. These properties can ultimately have a critical effect on the solubility and bioavailability of the final drug product. Here, the desmotropy of Albendazole forms I and II was investigated at the atomic level. Ultrafast magic angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) spectroscopy, together with powder X-ray diffraction, thermal analysis, and Fourier transform infrared spectroscopy, were performed on polycrystalline samples of the two solids in order to fully characterize and distinguish the two forms. High-resolution one-dimensional (1)H, (13)C, and (15)N together with two-dimensional (1)H/(1)H single quantum-single quantum, (1)H/(1)H single quantum-double quantum, and (1)H/(13)C chemical shift correlation solid-state NMR experiments under MAS conditions were extensively used to decipher the intramolecular and intermolecular hydrogen bonding interactions present in both solid forms. These experiments enabled the unequivocal identification of the tautomers of each desmotrope. Our results also revealed that both solid forms may be described as dimeric structures, with different intermolecular hydrogen bonds connecting the tautomers in each dimer.