Géza Regdon

Study of the recrystallization in coated pellets - Effect of coating on API crystallinity

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.

Surface Treatment of Indomethacin Agglomerates with Eudragit

Indomethacin is a widely used anti‐inflammatory drug with serious side‐effects. This drug was used as a model drug for the coating of agglomerates with a permeable film (Eudragit NE). The agglomeration of the crystals increased the flowability of the bulk crystals. The coating further improved the flowability, and also the uniformity of the mass of the filled capsules. The coating film also influenced the wetting of the samples. The coating decreased the surface free energy and therefore reduced the adhesion forces between both the dry and the wet particles. The modification of the flow properties and the even capsule filling can be explained by this phenomenon. Since coating film does not dissolve in the artificial gastric juice, the dissolution test was performed only in the artificial intestinal juice. The dissolution of indomethacin from the coated sample was changed significantly. Accordingly, coating of the crystals can be performed in order to protect the mucosa of the gastrointestinal tract or to promote the preparation of solid dosage form.

Effect of the surface free energy of materials on the lamination tendency of bilayer tablets

Dosage forms with fixed dose combinations of drugs is a frequent and advantageous mode of administration, but their production involves a number of technological problems. Numerous interactions in a homogeneous vehicle may be avoided through the use of layered tablets. The mechanical properties of these dosage forms depend on numerous process parameters and material characteristics. The aim of the present study was a detailed investigation of the relationships between the surface characteristics and deformation properties of tableting materials and the tendency of bilayer tablets to undergo lamination. Bilayer tablets were compressed from unlubricated materials with different plastic-elastic properties and surface free energies according to a mixed 2 and 3-level half-replicated factorial design. The results revealed that the surface characteristics play the main role in the lamination of layered tablets and the effect of the plastic-elastic behavior cannot be interpreted without a knowledge of these properties.

Indirect methods for determination of the protective effects of coating films on the surface of crystals

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.

From Mini to Micro Scale—Feasibility of Raman Spectroscopy as a Process Analytical Tool (PAT)

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—PLS) 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: 3.5 kg cores), the aim of the present work was to prove the robustness of the model by transferring the results to tablets coated in a micro scale pan coater (0.5 kg). 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 six different coating levels. Then, the amount of coating, which was predicted by the model, was compared with reference measurements using UV spectroscopy. Results For all six 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 squares of errors for calibration and prediction (root mean square of errors for calibration and prediction—RMSEC and RMSEP) were 0.335 mg and 0.392 mg, respectively, which means that the predictive power of the model is not dependent on the scale or the equipment. Conclusion The scale-down experiment showed that it was possible to transfer the PLS model developed on a mini scale coater to a micro scale coater.

Multivariate calibration of the degree of crystallinity in intact pellets by X-ray powder diffraction.

XRPD is the method of choice to determine crystalline content in an amorphous environment. While several studies describe its use on powders, little information is available on its performance on finished products. The methods use may be limited not only by the need of sample pretreatment and its validation but also by the propensity of some materials to recrystallize when exposed to heat or mechanical stress. In this work the authors describe an attempt at constructing a model based on the XRPD measurement of intact layered pellets using univariate methods based on peak heights and PLS regression. Results indicate that neither the goodness-of-fit (below 0.9 for all tested variables), nor the RMSEC values (above 5 for all tested variables) of any model based on peak height were good enough to consider them for everyday use. PLS regression however provided a model with improved characteristics (R(2)=0.9581, RMSEC=3.04) despite the low API content and individual loading characteristics also reflected the validity of the model. PLS analysis also indicated that a specific sample may be different in some formulation characteristic that did not register on other examinations. This further indicates the methods usefulness in the analysis of intact dosage forms.

Estimation of design space for an extrusion-spheronization process using response surface methodology and artificial neural network modelling

The application of the Quality by Design principles is one of the key issues of the recent pharmaceutical developments. In the past decade a lot of knowledge was collected about the practical realization of the concept, but there are still a lot of unanswered questions. The key requirement of the concept is the mathematical description of the effect of the critical factors and their interactions on the critical quality attributes (CQAs) of the product. The process design space (PDS) is usually determined by the use of design of experiment (DoE) based response surface methodologies (RSM), but inaccuracies in the applied polynomial models often resulted in the over/underestimation of the real trends and changes making the calculations uncertain, especially in the edge regions of the PDS. The completion of RSM with artificial neural network (ANN) based models is therefore a commonly used method to reduce the uncertainties. Nevertheless, since the different researches are focusing on the use of a given DoE, there is lack of comparative studies on different experimental layouts. Therefore, the aim of present study was to investigate the effect of the different DoE layouts (2 level full factorial, Central Composite, Box-Behnken, 3 level fractional and 3 level full factorial design) on the model predictability and to compare model sensitivities according to the organization of the experimental data set. It was revealed that the size of the design space could differ more than 40% calculated with different polynomial models, which was associated with a considerable shift in its position when higher level layouts were applied. The shift was more considerable when the calculation was based on RSM. The model predictability was also better with ANN based models. Nevertheless, both modelling methods exhibit considerable sensitivity to the organization of the experimental data set, and the use of design layouts is recommended, where the extreme values factors are more represented.

Implementation of an artificial neural network as a PAT tool for the prediction of temperature distribution within a pharmaceutical fluidized bed granulator.

In this study, a novel in-line measurement technique of the air temperature distribution during a granulation process using a conical fluidized bed was designed and built for the purpose of measuring the temperature under the Process Analytical Technology (PAT) and introduced to predict the establishment of temperature profiles. Three sets of thermocouples were used, placed at different positions covering the whole operating range, connected to data acquisition measurement hardware, allowing an in-line acquisition and recording of temperatures every second. The measurements throughout the fluidized bed were performed in a steady state by spraying a solution of PVP onto a lactose monohydrate powder bed in order to make predictions of the temperature distribution and the hydrodynamics of the bed during the granulation process using Artificial Neural Networks (ANNs) and to establish the different temperature profiles for different process conditions through the precise predicted information by the constructed, trained, validated and tested neural network. The models testing results showed a strong prediction capacity of the effects of process variables. Indeed, the predicted temperature values obtained with the ANN model were in good agreement with the values measured with in-line reference method and hence the method can have an application as a predictive control tool.

The Effect of Plasticizer on the Free Volume in Metolose Systems

The quality of the pharmaceutical film-forming material (Metolose) is crucial during the tablet-coating process. The aim of this study was to establish a connection between the concentration of the plasticizer (poly-ethylene-glycol, PEG) in the cast film and the free volume. We studied the o-Ps lifetime in a series of Metolose-PEG systems as a function of PEG concentration in the widest available range. The samples were thin films cast from a dispersion of Metolose in aqueous solution of PEG. The found concentration dependence of the free volume in the Metolose-PEG systems is compared with other physical-chemical properties of the samples.

Formulation and in vitro study of antibacterial vaginal suppositories

Vaginal suppositories frequently used in gynaecological therapy were studied. Several antibacterial pharmacons are used for the topical treatment of vaginitis of various origins. In view of the fact that the liberation of the given active substance and the subsequent therapeutic effect may be improved or inhibited by the vehicle, our aim was to find the optimal suppository base for vaginal suppositories containing sulfadimidine, chloramphenicol and gentamicin sulfate by means of in vitro experiments. On the basis of breaking hardness, disintegration time and spreading properties the French Suppocire NA product, and compositions of macrogols with lower molecular weight proved to be the best lipophilic and hydrophilic bases, respectively. Among the lipophilic bases the in vitro drug liberation of Suppocire NA was significantly better (P < 0.05) than the other lipophilic bases. This vehicle is recommended for the topical treatment of vaginitis, as these suppositories have the further advantage that they can easily be produced on a magistral, galenical or industrial scale as well.