Impact of excipients in the chronic toxicity of fluoxetine on the alga Chlorella vulgaris

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) widely used in the treatment of major depression. It has been detected in surface and wastewaters, being able to negatively affect aquatic organisms. Most of the ecotoxicity studies focused only in pharmaceuticals, though excipients can also pose a risk to non-target organisms. In this work the ecotoxicity of five medicines (three generic formulations and two brand labels) containing the same active substance (fluoxetine hydrochloride) was tested on the alga Chlorella vulgaris, in order to evaluate if excipients can influence their ecotoxicity. Effective concentrations that cause 50% of inhibition (EC50) ranging from 0.25 to 15 mg L−1 were obtained in the growth inhibition test performed for the different medicines. The corresponding values for fluoxetine concentration are 10 times lower. Higher EC50 values had been published for the same alga considering only the toxicity of fluoxetine. Therefore, this increase in toxicity may be attributed to the presence of excipients. Thus more studies on ecotoxicological effects of excipients are required in order to assess the environmental risk they may pose to aquatic organisms.

Thermal analysis and compatibility studies of prednicarbate with excipients used in semi solid pharmaceutical form

Differential Scanning Calorimetry (DSC), thermogravimetry/derivative thermogravimetry (TG/DTG) and infrared spectroscopy (IR) techniques were used to investigate the compatibility between prednicarbate and several excipients commonly used in semi solid pharmaceutical form. The thermoanalytical studies of 1:1 (m/m) drug/excipient physical mixtures showed that the beginning of the first thermal decomposition stage of the prednicarbate (T (onset) value) was decreased in the presence of stearyl alcohol and glyceryl stearate compared to the drug alone. For the binary mixture of drug/sodium pirrolidone carboxilate the first thermal decomposition stage was not changed, however the DTG peak temperature (T (peak DTG)) decreased. The comparison of the IR spectra of the drug, the physical mixtures and of the thermally treated samples confirmed the thermal decomposition of prednicarbate. By the comparison of the thermal profiles of 1:1 prednicarbate:excipients mixtures (methylparaben, propylparaben, carbomer 940, acrylate crosspolymer, lactic acid, light liquid paraffin, isopropyl palmitate, myristyl lactate and cetyl alcohol) no interaction was observed.

Compatibility studies between captopril and pharmaceutical excipients used in tablets formulations

Captopril (CAP) was the first commercially available angiotensine-converting enzyme (ACE) inhibitor. In the anti-hypertensive therapy is considered the selected drug has to be therapeutically effective together with reduced toxicity. CAP is an antihypertensive drug currently being administered in tablet form. In order to investigate the possible interactions between CAP and excipients in tablets formulations, differential scanning calorimetry (DSC) and thermogravimetric (TG) analysis completed by X-ray powder diffraction (XRPD) and Fourier transform infrared spectroscopy (FTIR) were used for compatibility studies. A possible drug-excipient interaction was observed with magnesium stearate by DSC technique.

Induction of ovulation in rabbits by adding Lecirelin to the seminal dose: In vitro and in vivo effects of different excipients.

This study evaluates the effect of Lecirelin (Dalmarelin®, Fatro, Italy) diluted in different excipients (benzilic alcohol, benzoic acid and paraben) added to a seminal dose on LH concentrations, progesterone concentrations and ovarian status in rabbits. The in vitro effect on spermatozoa was also tested. A total of 100 multiparous female rabbits were divided into 5 groups, which at the moment of AI, received 0.2 mL (5 μg/dose) intramuscular (im) inoculation of Lecirelin (control) or the same Lecirelin dose administered intravaginally (iv) with the seminal dose alone (Lecirelin group) or with benzilic alcohol (Lecirelin BA group), benzoic acid (Lecirelin BAc group) or parabens (Lecirelin PA group) as an excipient. After 7 days, 10 rabbits per group were euthanized to analyze their ovarian status. In the control group, a high LH peak was detected 30 min post AI, while in the iv groups a slight increase in LH occurred after 120 min. The ovulation and fertility rate was similar in control and Lecirelin groups, while the lowest fertility rate was detected in the Lecirelin BA group. In a second experiment, the semen samples collected from male rabbits were diluted in TALP (control) or mixed with the 5 μg of Lecirelin solutions used in the first experiment. The highest percentage of capacitated sperm (68.3%) was recorded in the Lecirelin PA. The lowest percentages were observed in the Lecirelin BA and BAc groups. In conclusion, the iv administration of Lecirelin represents an alternative method for simplifying rabbit insemination procedures.

The effect of selected water-soluble excipients on the dissolution of paracetamol and ibuprofen

The purpose of this investigation was to study the dissolution behavior of paracetamol and ibuprofen in the presence of a range of selected potential excipients. First, a pH-solubility profile was generated for both drugs, and the effect of changing hydrodynamic conditions on the intrinsic dissolution rate was investigated. It was established that both drugs dissolved according to the diffusion-layer model. Paracetamol solubility (approximately 20.3 mg mL -1) did not vary from pH 1.2-8.0, corresponding to the in vivo range in the gastrointestinal tract. Ibuprofen had an intrinsic solubility of approximately 0.06 mg mL-1, and pKa was calculated as 4.4. Second, the effects of selected potential excipients (lactose, potassium bicarbonate, sodium bicarbonate, sodium chloride, and tartaric acid) were evaluated by measuring the effect of the inclusion of each additive in the dissolution medium on drug solubility, drug intrinsic dissolution rate, and solution viscosity. The results were evaluated using the diffusion-layer model, and it was determined that for paracetamol, the collected data fitted the model for all the excipients studied. For ibuprofen, it was found that there were differences between the excipients that raised the solution pH above the pK a to those that did not. For the excipients raising the pH above the pKa, the effect on intrinsic dissolution rate was not as high as that expected from the change in drug solubility. It was postulated that this might be due to lack of penetration of the excipient into the drug boundary layer microenvironment. Formulators may calculate the effect of adding an excipient based on solubility increases but may not find the dissolution rate improvement expected. Copyright © 2005 Taylor & Francis Inc.

The influence of excipients on the diffusion of ibuprofen and paracetamol in gastric mucus

The aim of this study was to examine the diffusion of commonly administered analgesics, ibuprofen and paracetamol, through gastric mucus. As ibuprofen and paracetamol are often formulated with alkalising excipients, or are commonly co-administered with antacids that have been demonstrated to alter their absorption, diffusion was also studied in the presence of a range of soluble and insoluble antacids or buffering agents. The effect of pH, which has been demonstrated to modify the properties of mucus, was also studied. Mucus was a significant barrier to diffusion for both drugs, compared to an unstirred aqueous layer with diffusion rates significantly lower in the presence of a mucus barrier for both drugs; ibuprofen diffusion also demonstrated a significant increase in the lag time. Paracetamol diffusion was not significantly affected by addition of any antacid, whereas ibuprofen rates were affected and the diffusion lag time for ibuprofen was significantly reduced in all cases. Isolated increases in pH increased the rate and reduced the lag time for ibuprofen diffusion. It was shown that mucus acts as a passive barrier in the case of paracetamol diffusion, and an interactive barrier to ibuprofen diffusion. Changes in mucus viscosity at different pH values may be responsible for the observed changes in ibuprofen diffusion rate. © 2004 Elsevier B.V. All rights reserved.

The role of formulation excipients in the development of lyophilised fast-disintegrating tablets

Despite recent Success, many fast-disintegrating tablets (FDTs) still face problems of low mechanical strength, poor mouth-feel and higher disintegration times. This Study aimed to optimise FDTS using a progressive three-stage approach. A series of hardness, fracturability and disintegration time tests were performed on the formulations at each stage. During Stage 1, tablets were prepared in concentrations between 2% and 5% w/w, and were formulated at each concentration as single and combination bloom strength gelatin (BSG) using 75 and 225 BSGs. Analysis revealed that both hardness and disintegration time increased with an increase in gelatin concentration. A combination (5% gelatin) FDT comprising a 50:50 ratio of 75:225 BSGs (hardness: 13.7 +/- 0.9 N and disintegration time: 24.1 +/- 0.6 s) was judged the most ideal, and was carried forward to Stage II: the addition of the saccharides sorbitol, mannitol and sucrose in concentrations between 10% and 80% w/w. The best properties were exhibited by mannitol-containing formulations (50%-hardness: 30.9 +/- 2.8 N and disintegration time: 13.3 +/- 2.1 s), which were carried forward to the next stage: the addition of viscosity-modifying polymers to improve mouth-feel and aid pre-gastric retention. Addition of carbopol 974P-NF resulted in the enhancement of viscosity with a compromise of the hardness of the tablet, whereas Pluronic F127 (6%) showed an increase in disintegration time and viscosity with retention of mechanical propel-ties. (C) 2008 Elsevier B.V. All rights reserved.

Ordered mixing of drugs with particulate excipients

A novel direct compression tableting excipient has been made by recrystallisation of lactose. The particles produced had high porosity, high specific surface area and high surface roughness. The resistance to segregation of ordered mixes formed between a model drug; potassium chloride and the excipients recrystallised lactose, spray crystallised maltose-dextrose (Emdexl and a direct compacting sugar (Dipac) was studied using a vibrational segregation model. The highly porous excipients, Emdex and recrystallised lactose formed ordered mixes which did not segregate even at high accelerations and low frequencies whereas the relatively smooth excipient, Dipac, displayed marked segregation in most vibration conditions. The vibrations were related to practical conditions measured in pharmaceutical process machinery. The time required to form an ordered mix was inversely related to the stability of the mix when subjected to vibration. An ultracentrifuge technique was developed to determine the interparticle adhesion forces holding drug and excipient particles together as ordered units. Excipient powders such as Emdex and recrystallised lactose, which formed non-segregating ordered mixes, had high interparticle adhesion forces. Other ordered mixes that segregated when subjected to different vibration conditions were found to have large quantities of weekly-bound drug particles; such mixes included those with Dipac as the carrier excipient as well as those containing a high concentration of drug. The electrostatic properties of different drug and excipient powders were studied using a Faraday well and an electrometer. Excipient powders such as Emdex and recrystallised lactose which formed stable ordered mixes also had a widely different surface charge in comparison with drug particles, whereas Dipac had a similar surface charge to the drug particles and formed unstable ordered mixes. A specially constructed triboelectric charging apparatus based on an air cyclone was developed to increase the affinity of drug particles for different excipient particles. Using triboelectrification to increase the interparticle adhesion forces, the segregation tendencies of unstable ordered mixes were greatly reduced. The stability of ordered mixes is shown to be related to both the surface physical characteristics and the surface electrical properties of the constituent carrier (excipientl particles.

Compressed orally disintegrating tablets:excipients evolution and formulation strategies

Introduction: Orally disintegrating tablets (ODTs) have emerged as one of the novel solid oral dosage forms with a potential to deliver a wide range of drug candidates to both paediatric and geriatric patient populations. Of the plethora of available technologies, compression of excipients offers a cost-effective and translatable methodology for the manufacture of ODTs. Areas covered: The review is a modest endeavour from the authors to assemble literature published over the last couple of decades on formulation development of compressed ODT. It describes the main ODT excipients used since the introduction of this dosage form in the 1990s and explores the switch from cellulose-based excipients towards sugar/polyols. Furthermore, it unfolds the key properties of ODT fillers, binders and disintegrants with an emphasis on their advantages and drawbacks. The review also provides a critical assessment of the various strategies employed for performance enhancement of compressed ODT with a focus on the underlying mechanisms for fast disintegration and acceptable mechanical strength. Expert opinion: Recent increase in the total number of compression-based technologies for ODT development promises to reduce the manufacturing cost of this dosage form in the future. However, some of the developed methods may affect the stability of tablets due to susceptibility to moisture, collapse of pores or the generation of less stable polymorphs which require rigorous testing prior to commercialization. © 2013 Informa UK, Ltd.

Systematic screening of compressed ODT excipients:cellulosic versus non-cellulosic

The successful development of compressed ODTs utilises low compression forces to create a porous structure whereby excipients are added to enhance wicking/swelling action or provide strength to the fragile tablet framework. In this work, a systematic investigation comparing materials from two different categories was employed to understand their functionality in binary mixture tablets of the most commonly used diluent mannitol. Cellulose based excipients such as HPC (SSL-SFP), L-HPC (NBD-022) and MCC (Avicel PH-102) were compared with non-cellulosic materials such as PEO (POLYOX WSR N-10) and Crospovidone (XL-10). Pure excipient properties were studied using Heckel Plot, compressibility profile, SEM and XRPD, whereas the prepared binary mixture compacts were studied for hardness, disintegration time and friability. Results from our investigation provide insight into differences encountered in product performance of ODT upon inclusion of additional materials. For example, non-cellulosic excipients Polyox and Crospovidone showed higher plasticity (Py values 588 and 450MPa) in pure form but not in binary mixtures of mannitol. Cellulosic excipients, nonetheless, offer faster disintegration (<30 sec) specifically L-HPC and MCC tablets. Disintegration time for tablets with fully substituted-HPC was prolonged (200-500 sec) upon increasing concentration between 1-10% due to gelation/matrix formation. It can be concluded that despite the reasonably good plasticity of both cellulosic and non-cellulosic excipients in pure form, the mechanical strength in binary mixtures is negatively impacted by the fragmentation/fracture effect of mannitol. © 2014 Bentham Science Publishers.

Systematic screening of compressed ODT excipients : cellulosic versus non-cellulosic

The successful development of c ompressed ODTs utilises low compression force s to create a porous structure whereby excipients are added to enhance wicking/swelling action or p rovide strength to the fragile tablet framework. In this work, a systematic investigation comparing materials from two different categories was employed to understand their functionality in binary mixture tablets of the most commonly used diluent mannitol. Cellulose based excipients such as HPC (SSL-SFP), L-HPC (NBD -022) and MCC (Avicel PH -102 ) were compared with non -cellulosic materials such as PEO (POLYOX WSR N -10) and Crospovidone (XL -10). P ure excipient properties were studied using Heckel Plot, compre ssibility profile, SEM and XR PD, w hereas the prepared binary mixture compacts were studied for hardness, disintegration time and friability. Results from our investigation provide insight into differences encountered in product performance of ODT upon inclusion of additional materials. For example, non -cellulosic excipients Polyox and Crospovidone showed higher plasticity (Py values 588 and 450 MPa) in pure form but not in binary mixtures of mannitol . Cellulosic excipients, nonetheless, offer faster disintegration (

Excipients in medicines for children:scientific and regulatory paradigms

There is an ongoing debate over the use of pharmaceutical excipients in medicines for children, triggered by the increased number of formulations suitable for this target patient population. Pharmaceutical excipients can be regarded as essential / necessary enablers in formulation development. These are materials other than the 'active pharmaceutical ingredient' which are added to the formulation to achieve a specific function1. This may include aiding in the processing or manufacture of the drug delivery system such as lubricants or flow aids, controlling the release of the active ingredient to achieve modified release, enhance patient acceptability by improving taste of medicines or to develop easily swallowed dosage forms.

Development and validation of a simple and rapid capillary zone electrophoresis method for determination of nnrti nevirapine in pharmaceutical formulations

A simple and fast capillary zone electrophoresis (CZE) method has been developed and validated for quantification of a non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, in pharmaceuticals. The analysis was optimized using 10 mmol L-1 sodium phosphate buffer pH 2.5, +25 kV applied voltage, hydrodynamic injection 0.5 psi for 5 s and direct UV detection at 200 µm. Diazepam (50.0 µg mL-1) was used as internal standard. Under these conditions, nevirapine was analyzed in approximately less than 2.5 min. The analytical curve presented a coefficient of correlation of 0.9994. Limits of detection and quantification were 1.4 µg mL-1 and 4.3 µg mL-1, respectively. Intra- and inter-day precision expressed as relative standard deviations were 1.4% and 1.3%, respectively and the mean recovery was 100.81%. The active pharmaceutical ingredient was subjected to hydrolysis (acid, basic and neutral) and oxidative stress conditions. No interference of degradation products and tablet excipients were observed. This method showed to be rapid, simple, precise, accurate and economical for determination of nevirapine in pharmaceuticals and it is suitable for routine quality control analysis since CE offers benefits in terms of quicker method development and significantly reduced operating costs.