Microscopic and Spectroscopic Imaging and Thermal Analysis of Acrylates, Silicones and Active Pharmaceutical Ingredients in Adhesive Transdermal Patches.

Dermal or transdermal patches are increasingly becoming a noteworthy alternative as carriers for active pharmaceutical ingredients (APIs), which makes their detailed physicochemical evaluation essential for pharmaceutical development. This paper demonstrates mid-infrared (FTIR) and Raman spectroscopy with complementary microscopic methods (SEM, optical and confocal Raman microscopy) and differential scanning calorimetry (DSC) as tools for the identification of the state of model API (testosterone TST, cytisine CYT or indomethacin IND) in selected adhesive matrices. Among the employed spectroscopic techniques, FTIR and Raman may be used not only as standard methods for API identification in the matrix, but also as a means of distinguishing commercially available polymeric materials of a similar chemical structures. A novel approach for the preparation of adhesive polymers for the FTIR analysis was introduced. In silicone matrices, all three APIs were suspended, whereas in the case of the acrylic PSA, Raman microscopy confirmed that only IND was dissolved in all three acrylic matrices, and the dissolved fraction of the CYT differed depending on the matrix type. Moreover, the recrystallization of TST was observed in one of the acrylates. Interestingly, a DSC analysis of the acrylic patches did not confirm the presence of the API even if the microscopic images showed suspended particles.

Novel Binary Mixtures of Alkanolamine Based Deep Eutectic Solvents with Water-Thermodynamic Calculation and Correlation of Crucial Physicochemical Properties.

This paper demonstrates the assessment of physicochemical and thermodynamic properties of aqueous solutions of novel deep eutectic solvent (DES) built of tetrabutylammonium chloride and 3-amino-1-propanol or tetrabutylammonium bromide and 3-amino-1-propanol or 2-(methylamino)ethanol or 2-(butylamino)ethanol. Densities, speeds of sound, refractive indices, and viscosities for both pure and aqueous mixtures of DES were investigated over the entire range of compositions at atmospheric pressure and T = (293.15 ‒ 313.15) K. It was concluded that the experimental data were successfully fitted using the Jouyban-Acree model with respect to the concentration. Obtained results showed that this mathematical equation is an accurate correlation for the prediction of aqueous DES properties. Key physicochemical properties of the mixtures-such as excess molar volumes, excess isentropic compressibilities, deviations in viscosity, and deviations in refractive indices-were calculated and correlated by the Redlich-Kister equation with temperature-dependent parameters. The non-ideal behavior of the studied systems were also evaluated by using the Prigogine-Flory-Patterson theory and the results were interpreted in terms of interactions between the mixture components.

Preparation and Characterization of Indomethacin Supramolecular Systems with ß-Cyclodextrin in Order to Estimate Photostability Improvement.

Cyclodextrins have found wide application in contemporary chemistry, pharmacy and medicine. Because of their unique properties, cyclodextrins are constantly used in research on solubility or stability improvement, as well as other physicochemical properties of medicinal substances. Indomethacin (IND) is a photolabile molecule that also attracts the interest of researchers due to its therapeutic potential and the need to overcome its problematic photosensitivity. Supramolecular complexes of indomethacin with ß-cyclodextrin (CD) are already known, and they show greater stability compared to complexes with other types of cyclodextrins. So far, however, the sensitivity to light of physical mixtures and inclusion complexes in the solid phase has not been studied, and their various stoichiometries have not yet been investigated. Due to this fact, the aim of the present study is to obtain supramolecular systems (inclusion complexes and physical mixtures) of indomethacin with three different amounts of ß-cyclodextrin. Assessment of the photochemical stability of indomethacin-ß-cyclodextrin systems in the solid state is performed in order to find the best correlation between IND stability and the amount of CD. Comparative analysis of physicochemical degradation for stoichiometry systems [CD:IND] = [1:1], [0.5:1] and [0.1:1] is performed by using ultraviolet spectroscopy, transmission-FTIR, reflection-ATR-FTIR infrared spectroscopy and DSC calorimetry.

Spectroscopic evaluation on pseudopolymorphs of sodium naproxen.

This paper demonstrates the assessment of vibrational spectroscopy methods such as middle infrared, near infrared and Raman spectroscopy (FTIR, FT-NIR, Raman) for the identification of pseudopolymorphic forms of a model active pharmaceutical ingredient (API) - sodium naproxen (NpxNa). NpxNa, in the form of three different pseudopolymorphs, was investigated by methods dedicated for solid state characterization: DSC (differential scanning calorimetry), XPRD (powder X-ray diffraction), SEM (scanning electron microscopy) and Karl Fischer titration. Novelty in the results sourced in the usage of the method not applied so far to identify pseudopolymorphic forms of NpxNa, that is, FTIR and FT-NIR. Based on the obtained reproduceable results, various pseudopolymorphic forms were successfully evaluated. Spectroscopic data were correlated with DSC and XPRD results. It was concluded that the combination of band's variations visible on the spectra of pseudopolymorphic forms will allow to interpretate the results unequivocally in case of crucial stability tests of medicinal substance or during on-line pharmaceutical process development by FTIR, FT-NIR and Raman spectroscopy.

Studies on the influence of ß-cyclodextrin derivatives on the physical stability of famotidine.

The usage of Fourier transform infrared spectroscopy, near infrared spectroscopy, differential scanning calorimetry and microscopy is presented in this work focused on the exploration of the effect of CD on the physical stability of famotidine (FAM). The most significant information was achieved by analysis of the second derivatives of near infrared (NIR) spectra recorded. Changes in the shape of spectra derivatives allow to observe the improvement of physical stability of FAM with the usage of various supramolecular systems based on ß-cyclodextrin (CD) derivatives. The comparison was performed with the usage of maltodextrin in FAM mixtures. We found out that ß-cyclodextrin derivatives in the form of physical mixture and inclusion complexes successfully increased the physical stability of famotidine in solid state while maltodextrin does not show positive effect in imparting physical stability to famotidine.

Direct Human Contact with Siloxanes (Silicones) - Safety or Risk Part 1. Characteristics of Siloxanes (Silicones).

Siloxanes are commonly known as silicones. They belong to the organosilicon compounds and are exclusively obtained by synthesis. Their chemical structure determines a range of physicochemical properties which were recognized as unique. Due to the susceptibility to chemical modifications, ability to create short, long or complex polymer particles, siloxanes found an application in many areas of human life. Siloxanes differ in particle size, molecular weight, shape and chemical groups. As a result, this determines the different physico-chemical properties, that directly affect the safety or the risk of their use. The areas that can be a source of danger to human health will be commented in this paper.

Forced Degradation Studies of Ivabradine and In Silico Toxicology Predictions for Its New Designated Impurities.

All activities should aim to eliminate genotoxic impurities and/or protect the API against degradation. There is a necessity to monitor impurities from all classification groups, hence ivabradine forced degradation studies were performed. Ivabradine was proved to be quite durable active substance, but still new and with insufficient stability data. Increased temperature, acid, base, oxidation reagents and light were found to cause its degradation. Degradation products were determined with the usage of HPLC equipped with Q-TOF-MS detector. Calculations of pharmacological and toxicological properties were performed for six identified degradation products. Target prediction algorithm was applied on the basis of Hyperpolarization-activated cyclic nucleotide-gated cation channels, as well as more general parameters like logP and aqueous solubility. Ames test and five cytochromes activities were calculated for toxicity assessment for selected degradation products. Pharmacological activity of photodegradation product (UV4), which is known as active metabolite, was qualified and identified. Two other degradation compounds (Ox1 and N1), which were formed during degradation process, were found to be pharmacologically active.

Consequences of New Approach to Chemical Stability Tests to Active Pharmaceutical Ingredients.

There is a great need of broaden look on stability tests of active pharmaceutical ingredients (APIs) in comparison with current requirements contained in pharmacopeia. By usage of many modern analytical methods the conception of monitoring the changes of APIs during initial stage of their exposure to harmful factors has been developed. New knowledge must be acquired in terms of identification of each degradation products, especially volatile ones. Further research as toxicology prediction during in silico studies of determined and identified degradation products is necessary. In silico methods are known as computational toxicology or computer-assisted technologies which are used for predicting toxicology of pharmaceutical substances such as impurities or degradation products. This is a specialized software and databases intended to calculate probability of genotoxicity or mutagenicity of these substances through a chemical structure-based screening process and algorithm specific to a given software program. Applying of new analytical approach is proposed as the usage of PAT tools, XRD, HS-SPME GC-MS/MS, LC-MS/MS for stability testing. Described improvements should be taken into account in case of each drug existing already in the market as well as being implemented as new one.

Physical and Mechanical Evaluation of Silicone-Based Double-Layer Adhesive Patch Intended for Keloids and Scar Treatment Therapy.

Growing interest in silicone elastomers for pharmaceutical purposes is due to both their beneficial material effect for scar treatment and their potential as drug carriers. Regarding their morphological structure, silicone polymers possess unique properties, which enable a wide range of applicability possibilities. The present study focused on developing a double-layer adhesive silicone film (DLASil) by evaluating its physical and mechanical properties, morphology, and stability. DLASil suitability for treatment of scars and keloids was evaluated by measurement of tensile strength, elasticity modulus, and elongation. The results indicated that mechanical and physical properties of the developed product were satisfying.

Double layer adhesive silicone dressing as a potential dermal drug delivery film in scar treatment.

The present studies focused on the evaluation of design of an adhesive silicone film intended for scar treatment. Developed silicone double layer film was examined in terms of its future relevance to therapy and applicability on the human skin considering properties which included in vitro permeability of water vapor and oxygen. In order to adapt the patches for medical use in the future there were tested such properties as in vitro adhesion and occlusion related to in vivo hydration. From the silicone rubbers double layer silicone film was prepared: a non-adhesive elastomer as a drug carrier (the matrix for active substances - enoxaparin sodium - low molecular weight heparin) and an adhesive elastomer, applied on the surface of the matrix. The novel adhesive silicone film was found to possess optimal properties in comparison to commercially available silicone dressing: adhesion in vivo, adhesion in vitro - 11.79N, occlusion F=85% and water vapor permeability in vitro - WVP=105g/m(2)/24h, hydration of stratum corneum in vivoH=61-89 (RSD=1.6-0.9%), oxygen permeation in vitro - 119-391 cm(3)/m(2)/24 (RSD=0.17%). In vitro release studies indicated sufficient LMWH release rate from silicone matrix. Developed novel adhesive silicone films were considered an effective treatment of scars and keloids and a potential drug carrier able to improve the effectiveness of therapy.

Application of vibrational spectroscopy, thermal analyses and X-ray diffraction in the rapid evaluation of the stability in solid-state of ranitidine, famotidine and cimetidine.

This paper reports the study on applicability of Fourier transform infrared (FTIR), near-infrared (NIR) and Raman spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) for the estimation of the chemical stability and photostability of histamine H2-receptor antagonist substances. Ranitidine hydrochloride (RAN), famotidine (FAM) and cimetidine (CIM) were tested and differences in sensitivity were measured via soft independence modeling of class analogies (Simca) model. The low values of variations for FAM and CIM and high variations obtained for RAN using FTIR and NIR techniques indicated that these methods were suitable and applicable to classify the degradation of RAN. Examined methods are recommendable in the first technological stage of drug production, and the preclinical and clinical development of pharmaceuticals or their quality control.

Evaluation of the photoprotective effect of ß-cyclodextrin on the emission of volatile degradation products of ranitidine.

The process of the photo-excitation of ranitidine hydrochloride (RAN) in a solid state makes visible changes to its colour and generates an unpleasant odour. The purpose of the present study was to observe the protective effects of ß-cyclodextrin (CD) complexation as well as the effect of the mixture of two stoichiometries 1:1 and 1:2 (RAN:CD, IC) on the photostability of samples in a solid state. Samples of inclusion complexes (IC) and physical mixtures (PM) were prepared and irradiated for 48h in a Suntest CPS+ chamber. Irradiated samples were analyzed using nuclear magnetic resonance ((1)H NMR), infrared spectroscopy (FT-IR), the differential scanning calorimetry method (DSC) and thermogravimetry analysis (TGA). Volatiles were monitored with the use of headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS). The protective effect of CD was noticed with respect to IC, and also PM. Achieved photostabilization of complexed RAN against photodegradation could be explained due to either the inclusion of the furan part of RAN into the CD cavity as shown by the (1)H NMR ROESY (rotation frame nuclear Overhauser effect spectroscopy) spectrum or the screening effect of CD. FT-IR spectra, DSC curves and microscope images of irradiated samples of protected RAN did not indicate any physical changes, such as phase transfer.

Determination of API content in a pilot-scale blending by near-infrared spectroscopy as a first step method to process line implementation.

Near infrared (NIR) spectroscopy was used for estimation of powder blend homogeneity and manufacturing control of a medicinal product powder mixture containing active pharmaceutical ingredient (API). Aiming at initiating a Process Analytical Technology (PAT) activity, the first step was a stationary mode at-line evaluation. In this, the content of pharmaceutical active compound in the powder mixtures intended to the direct tabletting was estimated based on recorded NIR spectra. Five formulations containing different quantities of API were prepared and analyzed also by a reference method--UV-Vis spectroscopy. A chemometric model was developed for calculation of the API amount in the mixtures. The Principal Component Regression (PCR) and Partial Least Squares (PLS) algorithms were used to obtain a model useful in further implementation for the PAT recommendations, into in-line blending control.

Detection of some volatile degradation products released during photoexposition of ranitidine in a solid state.

Ranitidine (RAN) is on top of the list of prescribed drugs, due to its popularity as a selective H2-receptor antagonist, which efficiently decreases the amount of acid produced in the stomach. RAN is not stable both in a solid state and in a solution, which creates manufacturing problems, requires appropriate storage conditions, and results in a short drug shelf-life. The aim of this work was to study the emission of volatile degradation products generated during photoexposition of ranitidine hydrochloride in a solid state. Significant changes in volatile profile of irradiated RAN were detected using HS-SPME-GC-MS. Sixteen major peaks were noticed on the chromatograms of irradiated ranitidine and the structures of some compounds were elucidated, while the presence of acetaldoxime, thiazole, dimethylformamide, dimethylacetamide and 5-methylfurfural was confirmed by means of the analysis of the authentic standards.

Application of the near-infrared spectroscopy in the pharmaceutical technology.

Near-infrared (NIR) spectroscopy is currently the fastest-growing and the most versatile analytical method not only in the pharmaceutical sciences but also in the industry. This review focuses on recent NIR applications in the pharmaceutical technology. This article covers monitoring, by NIR, of many manufacturing processes, such as granulation, mixing or drying, in order to determine the end-point of these processes. In this paper, apart from basic theoretical information concerning the NIR spectra, there are included determinations of the quality and quantity of pharmaceutical compounds. Some examples of measurements and control of physicochemical parameters of the final medicinal products, such as hardness, porosity, thickness size, compression strength, disintegration time and potential counterfeit are included. Biotechnology and plant drug analysis using NIR is also described. Moreover, some disadvantages of this method are stressed and future perspectives are anticipated.

Technology of an adhesive silicone film as drug carrier in transdermal therapy. I: Analytical methods used for characterization and design of the universal elastomer layers.

Silicone polymers possess unique properties, which make them suitable for many different applications, for example in the pharmaceutical and medical industry. To create an adhesive silicone film, the appropriate silicone components have to be chosen first. From these components two layers were made: an adhesive elastomer applied on the skin, and a non-adhesive elastomer on the other side of the film. The aim of this study was to identify a set of analytical methods that can be used for detailed characterization of the elastomer layers, as needed when designing new silicone films. More specifically, the following methods were combined to detailed identification of the silicone components: Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (¹H NMR) and size exclusion chromatography with evaporative light scattering detector (SEC-ELSD). It was demonstrated that these methods together with a rheological analysis are suitable for controlling the cross-linking reaction, thus obtaining the desired properties of the silicone film. Adhesive silicone films can be used as universal materials for medical use, particularly for effective treatment of scars and keloids or as drug carriers in transdermal therapy.

pH-tunable equilibria in azocrown ethers with histidine moieties.

The crown ethers with electro- and photoactive azo moieties containing substituents with mobile protons such as in the -COOH groups of histidine, show unique effect of pH switched on/off presence of the azo form. The differences observed for the electrochemical behavior of azocrown ethers with N-acetylhistidine and imidazole moieties reveal the interference of a chemical reduction pathway in strongly acidified solutions. This chemical reduction process leads to the formation of a hydrazine derivative which can be detected by its further electroreduction on the electrode surface. The involvement of chemical reduction is seen clearly in the presence of mobile protons of the -COOH group and mercury as the electrode substrate. The behaviour of the N-acetylhistidine azomacrocyle is similar to that of compounds known to exist in quinone-hydrazone tautomeric equilibria.