The use of high performance anion exchange chromatography for the detection of counterfeit pharmaceutical products using the excipient content as a marker

The aim of the investigation described here was to examine the differences between genuine and counterfeit pharmaceutical products through the development of an analytical method capable of rigorously identifying the sugar-based excipients. High Performance Anion Exchange Chromatography, coupled to Pulsed Amperometric Detection (HPAEC-PAD), supported by Gas Chromatography-Mass Spectrometry (GC-MS), provided a method for the analysis of the carbohydrate based excipients. The analytical method was able to discriminate between the substitution patterns of a number of monosaccharides derived from commonly used excipients and these were compared for both genuine and counterfeit sildenafil citrate based products. The aim of the project was accomplished: the HPAEC-method was employed to analyse a counterfeit pharmaceutical ‘Herbal Viagra’

Drug-Excipient Compatibility Studies in Formulation Development: Current Trends and Techniques

The safety, efficacy, quality and stability of a formulation are the cornerstones of any new drug development process. In order to consistently maintain these attributes in a finished dosage form, it is important to have a comprehensive understanding of the physico-chemical characteristics of the active pharmaceutical ingredient (API), as well as all other components (e.g. excipients, manufacturing aids, packaging materials) of the drug product. In a new drug development process, a detailed characterization of the API and other formulation components is usually carried out during the preformulation stage. The preformulation stage involves characterization of several aspects of the API including solubility, dissolution, permeability, polymorph/salt screening, stability (solidstate and solution-state), ionization properties, particle size distribution, API-excipient compatibilities etc. [1]. Excipients are ubiquitous to virtually every pharmaceutical formulation, and facilitate the manufacture, stability, administration, delivery of the API, and/or provide other functionalities to the dosage form. Excipients are used to improve processing (e.g. improving powder flow [2, 3], powder compactibility [4-6] etc.), enhance aesthetics (e.g. identification, branding etc. [7]), optimize product performance (e.g. modified drug-release [8-11]), and/or to facilitate patient compliance (e.g. taste masking [12-15]). They may constitute anywhere from 1 to 99 % of the total formulation mass. Due to the intimate contact of the API with one or more excipients in a formulation, there exists a likelihood of physical and/or chemical interactions between them. Any such interactions may result in a negative impact on the physical, stability or performance attributes of the drug product [16, 17]. The choice of excipients is of crucial importance to avoid these negative effects, and to facilitate the development of a robust and an effective formulation [18-20]. Thus, for a rational selection of excipients, screening of excipient-API compatibility is recognized as an important aspect of formulation development. Moreover, the USFDA’s 21st century current Good Manufacturing Practices (cGMP) initiative and International Council on Harmonization (ICH) Q8 guidelines encourage the pharmaceutical manufacturers to apply Quality by Design (QbD) principles in their drug development process [21, 22]. These guidelines include expectations of a clear understanding of any interactions between the formulation components. Moreover, recent advances in various thermal and non-thermal analytical techniques have led to an improved efficiency in the detection, monitoring and prevention of the incompatibilities early in the drug development process [23, 24]. This article aims to provide a brief overview of the nature of drug-excipient incompatibilities; as well as current trends and techniques used to evaluate these compatibilities in formulation development

Melt-extruded polyethylene oxide (PEO) rods as drug delivery vehicles: Formulation, performance as controlled release devices and the influence of co-extruded excipients on drug release profiles

The utility of controlled release medication formulations lies in their ability to keep drugs at steady levels in the blood plasma of recipients and within the termini of the maximum and minimum effective therapeutic levels. This avoids the “ups” and “downs” of medication levels within the body which would have been the result had conventional immediate release tablets been administered instead. In the veterinary field, controlled release medications are essential¹ because of the logistical difficulties of administering drugs on a regular (e.g., daily) basis to animals. The chief advantages of controlled release veterinary medications lie in the ease with which they can be administered; decrease in stress for animals, owing to less need for rounding up and frequent dosing; and, most importantly for farmers, the reduced cost of treatment relative to that for a multiple dosage regime

European Paediatric Formulation Initiative (EuPFI)-Formulating Ideas for Better Medicines for Children.

© American Association of Pharmaceutical Scientists 2016, published by Springer US, available online at doi: https://doi.org/10.1208/s12249-016-0584-1The European Paediatric Formulation Initiative (EuPFI), founded in 2007, aims to promote and facilitate the preparation of better and safe medicines for children through linking research and information dissemination. It brings together the capabilities of the industry, academics, hospitals, and regulators within a common platform in order to scope the solid understanding of the major issues, which will underpin the progress towards the future of paediatric medicines we want.The EuPFI was formed in parallel to the adoption of regulations within the EU and USA and has served as a community that drives research and dissemination through publications and the organisation of annual conferences. The membership and reach of this group have grown since its inception in 2007 and continue to develop and evolve to meet the continuing needs and ambitions of research into and development of age appropriate medicines. Five diverse workstreams (age-appropriate medicines, Biopharmaceutics, Administration Devices, Excipients and Taste Assessment & Taste Masking (TATM)) direct specific workpackages on behalf of the EuPFI. Furthermore, EuPFI interacts with multiple diverse professional groups across the globe to ensure efficient working in the area of paediatric medicines. Strong commitment and active involvement of all EuPFI stakeholders have proved to be vital to effectively address knowledge gaps related to paediatric medicines, discuss potential areas for further research and identify issues that need more attention and analysis in the future.Peer reviewedFinal Accepted Versio

Kaempferol-Phospholipid Complex: Formulation, and Evaluation of Improved Solubility, In Vivo Bioavailability, and Antioxidant Potential of Kaempferol

The current work describes the formulation and evaluation of a phospholipid complex of kaempferol toenhance the latter’s aqueous solubility, in vitro dissolution rate, in vivo antioxidant and hepatoprotectiveactivities, and oral bioavailability. The kaempferol-phospholipid complex was synthesized using a freeze-drying method with the formulation being optimized using a full factorial design (32) approach. The resultsinclude the validation of the mathematical model in order to ascertain the role of specific formulation andprocess variables that contribute favorably to the formulation’s development. The final product wascharacterized and confirmed by Differential Scanning Calorimetry (DSC), Fourier Transform InfraredSpectroscopy (FTIR), Proton Nuclear Magnetic Resonance Spectroscopy (1H-NMR), and Powder X-rayDiffraction (PXRD) analysis. The aqueous solubility and the in vitro dissolution rate were enhanced comparedto that of pure kaempferol. The in vivo antioxidant properties of the kaempferol-phospholipid complex wereevaluated by measuring its impact on carbon tetrachloride (CCl4)-intoxicated rats. The optimizedphospholipid complex improved the liver function test parameters to a significant level by restoration of allelevated liver marker enzymes in CCl4-intoxicated rats. The complex also enhanced the in vivo antioxidantpotential by increasing levels of GSH (reduced glutathione), SOD (superoxide dismutase), catalase anddecreasing lipid peroxidation, compared to that of pure kaempferol. The final optimized phospholipidcomplex also demonstrated a significant improvement in oral bioavailability demonstrated by improvementsto key pharmacokinetic parameters, compared to that of pure kaempferol

Glucosamine HCl-based solid dispersions to enhance the biopharmaceutical properties of acyclovir

The objective of the work presented here was to assess the feasibility of using glucosamine HCl as a solid-dispersion (SD) carrier to enhance the biopharmaceutical properties of a BCS class III/IV drug, acyclovir (ACV). The solid-dispersions of acyclovir and glucosamine HCl were prepared by an ethanol-based solvent evaporation method. The prepared formulations characterized by photomicroscopy, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transforms infrared spectrophotometry (FTIR), powder x-ray diffractometry (PXRD) and drug content analysis. The functional characterization of ACV-SD was performed by aqueous solubility evaluation, dissolution studies, fasted versus fed state dissolution comparison, ex vivo permeability, and stability studies. Photomicroscopy and SEM analysis showed different surface morphologies for pure ACV, glucosamine HCl and ACV-SD. The physical-chemical characterization studies supported the formation of ACV-SD. A 12-fold enhancement in the aqueous solubility of ACV was observed in the prepared solid dispersions, compared to pure ACV. Results from in vitro dissolution demonstrated a significant increase in the rate and extent of ACV dissolution from the prepared ACV-SD formulations, compared to pure ACV. The rate and extent of ACV permeability across everted rat intestinal membrane were also found to be significantly increased in the ACV-SD formulations. Under fed conditions, the rate and extent of the in vitro dissolution of ACV from the formulation was appreciably greater compared to fasted conditions. Overall, the results from the study suggest the feasibility of utilizing glucosamine HCl as a solid dispersion carrier/excipient for enhancement of biopharmaceutical properties of acyclovir, and similar drugs with low solubility/permeability characteristics

The influence of fillers on theophylline release from clay matrices

Abstract: The objectives of this study were to investigate the suitability of magnesium aluminium silicate (MAS) (Veegum®) to control drug release of a model drug, theophylline, from tablet matrices. To this end, the performance of three commonly used fillers namely: lactose, microcrystalline cellulose (Avicel PH102; MCC), and pre-gelatinized starch, Starch 1500 PGS), were evaluated against Veegum®. The physico-mechanical properties of the tablet matrices were studied along with dissolution studies to determine the effect of single or binary mixtures of the excipients on the drug release pattern. A DSC hydration methodology was also employed to characterize the states of water present in the tablet matrices and to determine any impact on drug release. Formulations containing MAS alone produced compacts with the lowest hardness (4.5 kp) whereas formulations containing MCC alone produced the hardest tablets (17.2 kp). Dissolution studies suggested that matrices containing MAS alone released the theophylline quickest as compared to lactose, MCC or PGS. It was difficult to establish a trend of the bound and free water states in the tablet matrices; however the formulation containing only MAS had the highest bound water at 29 %. The results therefore show that theophylline does not interact with MAS. As such the dominant factor in controlling drug release using MAS requires interaction or intercalation with a cationic drug. In the absence of this however, other excipients can play a role in controlling drug release. Keywords: Veegum, clay matrices, DSC hydration, Magnesium aluminium silicate, filler

Transdermal evaluation of caffeine in different formulations and excipients

Background: The stratum corneum(SC) forms adifficultphysical barrier fordrugs to pass through the skin. Several strategieswere developed to overcome this barrier.Optimization of topical drug formulations by selected excipients may facilitate the penetration of drugs through the SC into the viable skin cells and ultimately into the systemic circulation. Methods: Here, both the influence of two formulations (a classic carbomer-based gel and a novel Pluronic® lecithin organo gel (PLO gel)) and selected excipients (ethanol, propylene glycol, diethylene glycol monoethyl ether, isopropyl myristate (IPM), and water) with or without the penetration enhancer miconazole nitrate on the transdermal penetration characteristics of caffeine were determined using an in vitro Franz diffusion cell setup. Results: Higher fluxes were observed for the carbomer-based gel compared to the PLO gel. Among the commonly used excipients, IPM showed the best penetration enhancing properties, while the presence of the penetration enhancer miconazole nitrate did not significantly alter the apparent skin permeation characteristics for caffeine. Conclusion: The high ethanol percentage in the carbomer-based gel could explain the results as supported by our excipient data.Moreover, IPMcould play a beneficial role in topical formulations as this excipient was responsible for a significant increase in the amount of caffeine penetrated through the skin. No overall statistical significant effect of the presence of miconazole nitrate as a penetration enhancer was observed