Josep M. Suñé-Negre

Application of the SeDeM Diagram and a new mathematical equation in the design of direct compression tablet formulation.

Application of the new SeDeM Method is proposed for the study of the galenic properties of excipients in terms of the applicability of direct-compression technology. Through experimental studies of the parameters of the SeDeM Method and their subsequent mathematical treatment and graphical expression (SeDeM Diagram), six different DC diluents were analysed to determine whether they were suitable for direct compression (DC). Based on the properties of these diluents, a mathematical equation was established to identify the best DC diluent and the optimum amount to be used when defining a suitable formula for direct compression, depending on the SeDeM properties of the active pharmaceutical ingredient (API) to be used. The results obtained confirm that the SeDeM Method is an appropriate system, effective tool for determining a viable formulation for tablets prepared by direct compression, and can thus be used as the basis for the relevant pharmaceutical development.

DNA delivery via cationic solid lipid nanoparticles (SLNs)

In recent years the use of solid lipid nanoparticles (SLNs) as transport systems for the delivery of drugs and biomolecules has become particularly important. The use of cationic SLNs developed by the technique of microemulsion, which are complexed with DNA in order to study their application as non-viral vectors in gene therapy, is reported. The nanoparticles are characterized by scanning electron microscopy and transmission electron microscopy (SEM and TEM), atomic force microscopy (AFM) and differential scanning calorimetry (DSC). Furthermore, the process of lyophilization of the samples and their stability was studied. The nanoparticles obtained presented a particle size of 340 nm with a positive surface charge of 44 mV and the capability of forming lipoplexes with DNA plasmids was stated.

Optimization of parameters of the SeDeM Diagram Expert System: Hausner index (IH) and relative humidity (%RH)

As a methodology for characterizing substances in relation to their viability in direct compression, the SeDeM Diagram Expert System may be considered an open system in terms of the number of parameters applied and the optimization of these parameters. With the experience acquired from applying the SeDeM Diagram, in this study, we propose optimizing the parameters corresponding to the Hausner index (IH) and relative humidity (%HR) in order to simplify the mathematical calculation, so that it provides reliable data that can be extrapolated. The proposed optimization does not involve a conceptual change in the parameters considered nor a significant change in the results obtained compared with the previous calculation methodology initially established for the SeDeM Diagram Expert System, which means that the conclusions obtained by applying this method are equivalent.

Relationships between surface free energy, surface texture parameters and controlled drug release in hydrophilic matrices

The study of controlled release and drug release devices has been dominated by considerations of the bulk or average properties of material or devices. Yet the outermost surface atoms play a central role in their performance. The objective of this article has been to characterize the surface of hydrophilic matrix tablets using the contact angle (CA) method to ascertain the surface free energy, and atomic force microscopy (AFM) and confocal microscopy (CM) for the physical characterization of the surface of the hydrophilic matrix. The surface free energy results obtained show that hydroxypropylmethylcellulose K15M hinders the spreading of water on the surface of the tablet, such that the concentration of HPMC K15M increases the reaction rate of the hydrophobic interactions between the chains of HPMC K15M which increases with respect to the rate of penetration of water into the tablet. In this study, we developed a new method to characterize the swelling of the tablets and established a relationship between the new method based on microswelling and the swelling ratio parameter. The surface texture parameters have been determined and the morphology of the tablets of the different formulations and the evolution of the surface morphology after interacting with the water, swelling and forming a gel layer were characterized. This work represents significant progress in the characterization of matrix tablets.

A new optimized formulation of cationic solid lipid nanoparticles intended for gene delivery: Development, characterization and DNA binding efficiency of TCERG1 expression plasmid

Solid lipid nanoparticles (SLNs) are being considered as a new approach for therapeutics for many known diseases. In addition to drug delivery, their use as non-viral vectors for gene delivery can be achieved by the inclusion of cationic lipids, which provide a positive surface potential that favours binding to the DNA backbone. This work is based on the idea that the optimization of the components is required as the first step in simplifying the qualitative and quantitative composition of SLNs as much as possible without affecting the essential properties that define SLNs as optimal non-viral vectors for gene delivery. We selected the best lipids and surfactants in terms of particle size and zeta potential and characterized the properties of the resulting nanoparticles using X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). The SLNs had a particle size of approximately 120 nm and a positive surface charge of 42 mV. In addition, we analysed the main physicochemical characteristics of the bulk components of the nanoparticles using X-ray diffraction (XRD), differential scanning calorimetry (DSC) and mass spectrometry (MS). The suitability of the optimized SLNs for DNA binding was evaluated after the lyophilisation process using a carboxyl-terminal region of the TCERG1 gene, a human factor that has been implicated in several diseases. We show that the SLNs presented high efficiency in the binding of DNA, and importantly, they presented no toxicity when assayed in an in vivo system.

New classification of directly compressible (DC) excipients in function of the SeDeM Diagarm Expert System

As a methodology for characterizing substances with regard to its viability in direct compression, the SeDeM Diagram Expert System may be considered a new tool in terms of the number of parameters applied and its optimization. The paper is based on the experimental SeDeM characterization study of 51 directly compressible (DC) excipients. After selecting the parameters, and comparing the corresponding results, the choices available within the SeDeM Expert System could be expanded. Through applied variants, the maximum and optimal values of the DC diluent excipient were precisely defined and the mathematical limits of the parameters, functions and parametric indices that define the level of direct compressibility were established. These studies have allowed us to propose a new classification of excipients CD based on its rheological and compressibility capability, resulting in a periodic table of CD excipients. It has been determined that the best excipient for direct compression should have an index of good compression (IGC) of 8.832.

Preformulation and characterization of a lidocaine hydrochloride and dexamethasone sodium phosphate thermo-reversible and bioadhesive long-acting gel for intraperitoneal administration.

The search for new formulations of anaesthetic agents that allow a localized administration and provide a prolonged effect is of great interest in the multimodal management of postoperative pain. The pre-formulation and characterization of a lidocaine and dexamethasone thermosensitive and bioadhesive long-acting gel for intraperitoneal administration was done as a tool in the management of pain in abdominal surgeries. The pre-formulation process was conducted by a systematic variation of the concentration of the different polymers, until setting it, in a suitable concentration that allowed an adequate gelation temperature. The poloxamer 407 (P407) was used as the main polymer; hydroxypropyl methylcellulose (HPMC) as the bioadhesive agent and polyvinyl pyrrolidone (PVP) to adjust the gelation temperature and physicochemical properties. The formulations were characterized by gelation temperature, pH, viscosity at 25°C and 37°C, gelation time, density and osmolality. Gelation temperature was decreased when increasing the concentration of hydroxypropyl methylcellulose and poloxamer 407, this effect was also observed when adding lidocaine hydrochloride and dexamethasone sodium phosphate to the formulations. The gelation temperature did not have statistically significant relation with the PVP concentration (P-value of 0.6797), even though, there is a tendency in the gelation temperature by varying it. Between the developed formulations, the 12.5/3.3/0.4% (P407/HPMC/PVP) formulation presents an appropriate gelation temperature, a suitable viscosity for administration by syringe, an adequate and stable pH and osmolality to prevent tissue damage and a correct gelation time that allowed the formation of a prolonged release implant.

Authentication of gold nanoparticle encoded pharmaceutical tablets using polarimetric signatures.

The counterfeiting of pharmaceutical products represents concerns for both industry and the safety of the general public. Falsification produces losses to companies and poses health risks for patients. In order to detect fake pharmaceutical tablets, we propose producing film-coated tablets with gold nanoparticle encoding. These coated tablets contain unique polarimetric signatures. We present experiments to show that ellipsometric optical techniques, in combination with machine learning algorithms, can be used to distinguish genuine and fake samples. To the best of our knowledge, this is the first report using gold nanoparticles encoded with optical polarimetric classifiers to prevent the counterfeiting of pharmaceutical products.

Development and Validation of a Stability Indicating RP-HPLC Method for Hydrocortisone Acetate Active Ingredient, Propyl Parahydroxybenzoate and Methyl Parahydroxybenzoate Preservatives, Butylhydroxyanisole Antioxidant, and Their Degradation Products in a Rectal Gel Formulation.

A stability indicating method was established through a stress study, wherein different methods of degradation (oxidation, hydrolysis, photolysis, and temperature) were studied simultaneously to determine the active ingredient hydrocortisone acetate, preservatives propyl parahydroxybenzoate, and methyl parahydroxybenzoate, antioxidant butylhydroxyanisole (BHA), and their degradation products in a semisolid dosage gel form. The proposed method was suitably validated using a Zorbax SB-Phenyl column and gradient elution. The mobile phase consisted of a mixture of methanol, acetonitrile, and water in different proportions according to a planned program at a flow rate of 1.5 mL/min. The diode array detector was set at 240 nm for the active substance and two preservatives, and 290 nm for BHA. The validation study was conducted according to International Conference on Harmonization guidelines for specificity, linearity, repeatability, precision, and accuracy. The method was used for QC of hydrocortisone acetate gel and for the stability studies with the aim of quantifying the active substance, preservatives, antioxidant, and degradation products. It has proved to be suitable as a fast and reliable method for QC.

Approach to design space from retrospective quality data.

Abstract Context: Nowadays, the entire manufacturing process is based on the current GMPs, which emphasize the reproducibility of the process, and companies have a lot of recorded data about their processes. Objective: The establishment of the design space (DS) from retrospective data for a wet compression process. Materials and methods: A design of experiments (DoE) with historical data from 4 years of industrial production has been carried out using the experimental factors as the results of the previous risk analysis and eight key parameters (quality specifications) that encompassed process and quality control data. Results: Software Statgraphics 5.0 was applied, and data were processed to obtain eight DS as well as their safe and working ranges. Discussion and conclusion: Experience shows that it is possible to determine DS retrospectively, being the greatest difficulty in handling and processing of high amounts of data; however, the practicality of this study is very interesting as it let have the DS with minimal investment in experiments since actual production batch data are processed statistically.