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Cyclization of tert-anilines with a properly substituted vinyl moiety by the tert-amino effect affords fused pyridines. This type of ring closure reaction of 5-morpholino-4-vinylpyridazinones and a benzene analogue was investigated by differential scanning calorimetry (DSC) measurements. The structure of products was confirmed by spectroscopic and microanalytical methods. The enthalpy values and heats of reactions were obtained from the thermograms by integrating the peak area corresponding to the ring-closure reaction, and by semiempirical (PM3) and DFT (density function theory) calculations, respectively.

Mannitol and sorbitol are widely used in the pharmaceutical and food industry. There are some technological procedures such as spray-drying, freeze-drying, tablet compression, during which there is a possibility of heat effect. The purpose of this work was to study the thermal properties of sorbitol, mannitol and their mixtures. Furthermore, these materials and their tablet pressing were studied after melting and solidification. The results of the study prove that the use of sorbitol or mannitol alone is disadvantageous in melt technology. The use of mannitol is limited because of its high melting point (165°C) and the polymorph transition after melting. Sorbitol (melting point: 96.8°C) vitrifies from melt, therefore it is hard to handle during further processing. The melting point of the eutectic mixture (1.8% mannitol and 98.2% sorbitol) was 93.6°C. This mixture was unsuited for pressing because of its glassy property. Our results showed that the most favourable composition was the mixture of 30% mannitol and 70% sorbitol (melting point: 131.8°C) for tablet formulation. This mixture can be recommended for the formulation of such lozenge and hard candy tablets, where the active ingredient decomposes at higher temperature (>131.8°C).

In pharmaceutical practice it is important and useful to know the crystallinity of materials and to monitor it during formulation development, production processes and storage. The purpose of this study was to assess the quantitative capability of DSC for determining crystallinity in crystalline/amorphous powder mixtures and to compare the accuracy of the DSC method with that of conventional powder X-ray diffraction. Alpha-lactose monohydrate was chosen as the model material. On the basis of this study it can be concluded, that DSC method can be applied safely for semiquantitative evaluation of the crystallinity of lactose samples consisting of an amorphous content higher than 20%.

Cyclodextrin complexation was applied to achieve better aqueous solubility of the drug and to formulate suppositories. Binary products were prepared in several mole ratios by two different methods. The dissolution profiles and in vitro membrane diffusion behaviour of the compositions were investigated. Thermoanalytical studies were performed in order to confirm inclusion complex formation. Compositions were selected for further detailed investigations and for incorporation into suppository dosage form.

The extents of the protective effects of coating films on the surface of crystals were determined. Three different samples were made with different quantities of coating fluid (Sepifilm LP 010 in 10% aqueous solution). Since the atomizing rate was constant, the coating time increased in parallel with the volume of coating fluid applied. The direct measurement of film thickness and smoothness is very difficult, and therefore indirect methods were used. Dimenhydrinate was chosen as model drug; this is a heat-sensitive antihistamine with a low melting point. This temperature can be reached during the tableting process. The behaviour of samples on exposure to heat was examined by differential scanning calorimetry. The water uptakes of the samples were determined with an Enslin apparatus. Plasticity was studied with an instrumented tablet machine. These indirect methods (thermal conductivity, water uptake and plasticity measurements) revealed connections between the results of the various experiments. An overlong coating time decreased the protective effect of the coating film.

Dimenhydrinate is a heat-sensitive antihistamine with a low melting point. The heat-sensitive feature is of importance if direct compression is used. Direct measurement of the heat originating in the texture of tablets during compression is very difficult. Thermoanalytical methods were used as indirect methods to describe the changes in material properties at high temperature: differential scanning calorimetry, thermomicroscopy and thermogravimetric analysis. Film coating method is widely used in pharmaceutical technology. A fluidized bed apparatus was applied to coat the crystals. The coating film forming agent was hydroxy-propyl-methylcellulose (HPMC), which is a gastric-soluble polymer. Thermoanalytical measurements reveal that dimenhydrinate crystals are sensitive to heat. Film coating method does not alter the shape of the DSC curve of dimenhydrinate, but increases the melting point. The presence of a macromolecular film reduces the thermal conductivity, because it separates the particles.

The determination of film thickness is of prime importance in the quality assurance of coated pharmaceutical preparations. The rapid measurement of this parameter is problematic for multi-particulate pellet systems. The aim of this study was to apply the Raman spectroscopic method for the determination of the thickness of polymer coating on pellets. The change of Raman intensity was compared with measured film thickness, which was calculated from the change of the geometric parameters of the pellets, measured with an image-analyzing system. The results revealed that despite some difficulties Raman spectroscopy is a suitable method for the fast and accurate determination of film thickness on multi-particulate systems.

Although several methods have been investigated to measure the film thickness of tablets and its correlation with the dissolution behavior, much fewer such investigations exist for pharmaceutical pellets.To study the possibility of measuring the film thickness and predicting the dissolution behavior of pellets produced in different fluid bed equipments with Raman spectroscopy.Pyridoxine hydrochloride-layered pellets were produced and coated in two different Strea-1 equipments. Raman spectra were collected and analysed to set up a calibration model based on the film thickness data calculated from Camsizer analysis results. Dissolution tests were done according to Ph. Eur. standards.Raman spectroscopy proved to be a good tool in the measurement of film thickness. Polymer weight gain showed a linear correlation with film thickness but was a poor predictor of dissolution results below a threshold value.The Raman spectroscopic measurement of a small sample can provide accurate data of the film thickness. The investigation suggests that a threshold value might exist for the film thickness above which it can be used to judge future dissolution results.

Introduction: The focus of this work was to produce matrix pellets made by extrusion/ spheronization using two types of equipment. The aim was to accomplish the laboratory-scale I process that has been already optimized and accepted with another type of equipment (laboratory-scale II).Methods: A matrix pellet formulation consisting of MCC, Eudragit NE 30D and diclofenac sodium was used in the two types of equipment. Physico-chemical parameters and the dissolution profiles of the pellets in phosphate buffer pH 6.8 were compared.Results: Pellets from both processes were similar in shape and tensile strength. They differed in particle size and dissolution profile. This may be contributed to different spheronization conditions.

Coated diltiazem hydrochloride-containing pellets were prepared using the solution layering technique. Unusual thermal behavior was detected with differential scanning calorimetry (DSC) and its source was determined using thermogravimetry (TG), X-ray powder diffraction (XRPD) and hot-stage microscopy. The coated pellets contained diltiazem hydrochloride both in crystalline and amorphous form. Crystallization occurs on heat treatment causing an exothermic peak on the DSC curves that only appears in pellets containing both diltiazem hydrochloride and the coating. Results indicate that the amorphous fraction is situated in the coating layer. The migration of drugs into the coating layer can cause changes in its degree of crystallinity. Polymeric coating materials should therefore be investigated as possible crystallization inhibitors.

Background: Active coating is an important unit operation in the pharmaceutical industry. The quality, stability, safety and performance of the final product largely depend on the amount and uniformity of coating applied. Active coating is challenging regarding the total amount of coating and its uniformity. Consequently, there is a strong demand for tools, which are able to monitor and determine the endpoint of a coating operation. In previous work, it was shown that Raman spectroscopy is an appropriate process analytical tool (PAT) to monitor an active spray coating process in a pan coater [1]. Using a multivariate model (Partial Least Squares) the Raman spectral data could be correlated with the coated amount of the API diprophylline. While the multivariate model was shown to be valid for the process in a mini scale pan coater (batch size: 3.5kg cores), the aim of the present work was to prove the robustness of the model by transferring the results to tablets coated to a micro scale pan coater (0.5kg). Method: Coating experiments were performed in both, a mini scale and a micro scale pan coater. The model drug diprophylline was coated on placebo tablets. The multivariate model, established for the process in the mini scale pan coater, was applied to the Raman measurements of tablets coated in the micro scale coater for 6 different coating levels. Then, the amount of coating, which was predicted by the model, was compared with measurements using UV spectroscopy. Results: For all the 6 coating levels the predicted coating amount was equal to the amounts obtained by UV spectroscopy within the statistical error. Thus it was possible to predict the total coating amount with an error smaller than 3.6%. The root mean square of errors for calibration and prediction (RMSEC and RMSEP) was 0.335mg and 0.392mg which means that the model's predictive power is not dependent on the scale or the equipment. Conclusion: The scale-down experiment showed that it was possible to transfer the model developed on a mini scale coater to a micro scale coater. References: [1] J. Muller et al., Feasibility of Raman spectroscopy as PAT tool in active coating, Drug Dev Ind Pharm (2010) 36, 234-243. Acknowledgment: This work was supported by TAMOP-4.2.1/B-09/1/KONV-2010-0005(Hungary), P-MOB/817 (Hungary) and DAAD Project PPP Ungarn 50430305 (Germany).

Sugar esters (SEs) are widely used in the pharmaceutical and food industries. They have a wide range of HLB values (1–16), and hence they can be applied as surfactants, or as solubility or penetration enhancers. SEs can be employed in hot-melt technology, because their melting points are low and they decompose only above 220 °C. The aims of this work were to study the thermal properties of SEs and to demonstrate differences between SEs with various HLB values. The results revealed that SEs with high or medium HLB values were vitrified by melting. Their glass transitions ( T g ) were determined by modulated differential scanning calorimetry. To visualize the changes in the samples during heating, hot-stage microscopy was used. Hydrophilic SEs were only softened, while lipophilic SEs were melted by heating. After melting and solidification, SEs have partially amorphous layered structures which slowly crystallize in time. Time-dependent solid-state changes (crystalline and amorphous phases) were observed, and analysed by means of differential scanning calorimetry and X-ray powder diffraction.

The plasticizing effects of poly(ethylene glycol) (PEG 400) on methylcellulose (Metolose) cast films were studied by conventional physicochemical methods and positron annihilation spectroscopy. The PEG concentrations relative to the total polymer content were varied within the range 0–75% (w/w). At low concentrations (below 33.3%, w/w), the plasticizer was found to build in into the methylcellulose structure. On the other hand, at higher concentrations (above 50%, w/w), it formed small separate phases in the films. Positron annihilation spectroscopy (PALS) was applied to track the Metolose–PEG interaction. Controlled ageing of Metolose–PEG films at room temperature and at 75% RH revealed a significant difference between the ageing processes of the monophase and those of the separate phase films. The ageing involves two steps in both cases: a fast and a slow one. The PALS measurements demonstrated that the slow process is hindered in the phase-separated samples.

In pharmaceutical technology, film-forming agents are often applied in solution during the preparation of solid dosage forms. A wide range of polymers have already been examined, but many of the effects of the applied solvent on the properties of the film are still not fully known. The study of these phenomena might be of great help in the preparation of better films. In the present study, the frequently used polymer hydroxypropyl-cellulose was examined in water and ethanol. The latter solvent exhibits better wetting properties for this polymer. It was found that the use of ethanol enhanced the processibility because of the easier atomization and the shorter drying period. Properties characteristic of the chemical nature (wetting, surface free energy and thermal properties) and the physical behaviour (deformation process) of the poured films were studied. Relevant differences were detected only in the mechanical parameters. The sizes of the free volume holes in the differently prepared polymers were also determined, but this parameter proved irrelevant as concerns alterations of the breaking process. The explanation of the differences processibility of the films might be the different strengths of binding between the macromolecular chains. This phenomenon can also explain the different degrees of hydration of the polymer and the changes in the drying process.

Crystals of dimenhydrinate as a model drug were used for crystal coating, a method that can be applied to increase the flowability of a material and facilitate the tablet making. An increase in particle size was observed during the film coating. The change in shape of the coated particles was also examined. Some physicochemical parameters changed during coating, e.g. the surface free energy parameters and the wetting of the samples. The amount of coating material (and therefore the coating time) influenced several parameters (the shape of the particles, the flow properties and surface free energy parameters, compressibility and compactibility). Several parameters of prepared tablet (porosity, breaking hardness) were examined. Accordingly, coating of the crystals can be performed in order to enhance the handling of a material with insufficient properties for tablet making.

Our research has a double purpose. On the one hand, doctors have expressed the need to formulate a rectal suppository dosage form from diuretic ethacrynic acid, which would add to the choice of treatment methods and thereby increase the possibilities of individual cure. On the other hand, the liberation and thereby the bioavailability of poorly-soluble ethacrynic acid needs to be enhanced, and for this purpose solubility-increasing additives new to rectal therapy were used. Solutol HS 15, Cremophor RH 40, and Cremophor RH 60 were used as additives in concentrations of 1, 3, 5, and 10%. The quantity of drug released changed as a function of additive concentration. Depending on the acceptor phase, the best results were achieved with an additive concentration of 1-3%, which is related to the optimal additive quantity accumulated on the boundary surface.

The majority of active agents used in medicinal therapy belong to category BCS II, which means that they have poor dissolution and good absorption properties, thus their absorption can be controlled and promoted first of all with various formulation technologies. [...]

Coated dosage forms in which the active pharmaceutical ingredient (API) is incorporated in the film layer in order to achieve rapid release have become very common in recent years. [...]

Coated multiparticulate systems are increasingly popular on the market. Their manufacture in a fluid bed often requires polymer binders. [...]