Predicting Drug Release Rate of Implantable Matrices and Better Understanding of the Underlying Mechanisms through Experimental Design and Artificial Neural Network-Based Modelling.

There is a growing interest in implantable drug delivery systems (DDS) in pharmaceutical science. The aim of the present study is to investigate whether it is possible to customize drug release from implantable DDSs through drug-carrier interactions. Therefore, a series of chemically similar active ingredients (APIs) was mixed with different matrix-forming materials and was then compressed directly. Compression and dissolution interactions were examined by FT-IR spectroscopy. Regarding the effect of the interactions on drug release kinetics, a custom-made dissolution device designed for implantable systems was used. The data obtained were used to construct models based on artificial neural networks (ANNs) to predict drug dissolution. FT-IR studies confirmed the presence of H-bond-based solid-state interactions that intensified during dissolution. These results confirmed our hypothesis that interactions could significantly affect both the release rate and the amount of the released drug. The efficiencies of the kinetic parameter-based and point-to-point ANN models were also compared, where the results showed that the point-to-point models better handled predictive inaccuracies and provided better overall predictive efficiency.

Investigation of Surface Properties and Free Volumes of Chitosan-Based Buccal Mucoadhesive Drug Delivery Films Containing Ascorbic Acid.

Nowadays, the buccal administration of mucoadhesive films is very promising. Our aim was to prepare ascorbic acid-containing chitosan films to study the properties and structures important for applicability and optimize the composition. During the formulation of mucoadhesive films, chitosan as the polymer basis of the film was used. Ascorbic acid, which provided the acidic pH, was used in different concentrations (2-5%). The films were formulated by the solvent casting method. The properties of films important for applicability were investigated, such as physical parameters, mucoadhesive force, surface free energy, and breaking strength. The fine structure of the films was analyzed by atomic force microscopy, and the free volume was analyzed by PALS, which can be important for drug release kinetics and the location of the drug in the film. The applicability of the optimized composition was also tested with two different types of active ingredients. The structure of the films was also analyzed by XRPD and FTIR. Ascorbic acid can be used well in chitosan films, where it can function as a permeation enhancer when reacting to chitosan, it is biodegradable, and can be applied in 2% of our studies.

Effects of Sucrose Palmitate on the Physico-Chemical and Mucoadhesive Properties of Buccal Films.

In our current research, sucrose palmitate (SP) was applied as a possible permeation enhancer for buccal use. This route of administration is a novelty as there is no literature on the use of SP in buccal mucoadhesive films. Films containing SP were prepared at different temperatures, with different concentrations of SP and different lengths of hydroxypropyl methylcellulose (HPMC) chains. The mechanical, structural, and in vitro mucoadhesive properties of films containing SP were investigated. Tensile strength and mucoadhesive force were measured with a device and software developed in our Institute. Positron annihilation lifetime spectroscopy (PALS) and X-ray powder diffractometry (XRPD) were applied for the structure analysis of the films. Mucoadhesive work was calculated in two ways: from the measured contact angle and compared with direct mucoadhesive work, which measured mucoadhesive force, which is direct mucoadhesion work. These results correlate linearly with a correlation coefficient of 0.98. It is also novel because it is a new method for the determination of mucoadhesive work.

Optimization of the Production Process and Product Quality of Titanate Nanotube-Drug Composites.

Recently, there has been an increasing interest in the application of nanotubular structures for drug delivery. There are several promising results with carbon nanotubes; however, in light of some toxicity issues, the search for alternative materials has come into focus. The objective of the present study was to investigate the influence of the applied solvent on the composite formation of titanate nanotubes (TNTs) with various drugs in order to improve their pharmacokinetics, such as solubility, stability, and bioavailability. Composites were formed by the dissolution of atenolol (ATN) and hydrochlorothiazide (HCT) in ethanol, methanol, 0.01 M hydrochloric acid or in ethanol, 1M sodium hydroxide, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), respectively, and then they were mixed with a suspension of TNTs under sonication for 30 min and vacuum-dried for 24 h. The structural properties of composites were characterized by SEM, TEM, FT-IR, differential scanning calorimetry (DSC), thermogravimetric (TG) analysis, and optical contact angle (OCA) measurements. Drug release was determined from the fast disintegrating tablets using a dissolution tester coupled with a UV-Vis spectrometer. The results revealed that not only the good solubility of the drug in the applied solvent, but also the high volatility of the solvent, is necessary for an optimal composite-formation process.

Standpoint on the priority of TNTs and CNTs as targeted drug delivery systems.

Conventional drug delivery systems have limitations according to their toxicity and poor solubility, bioavailability, stability, and pharmacokinetics (PK). Here, we highlight the importance of functionalized titanate nanotubes (TNTs) as targeted drug delivery systems. We discuss the differences in the physicochemical properties of TNTs and carbon nanotubes (CNTs) and focus on the use of functionalization to improve their characteristics. TNTs are promising materials for drug delivery systems because of their superb properties compared with CNTs, such as their processability, wettability, and biocompatibility. Functionalization improves nanoparticles (NPs) via their surface modification and enables them to achieve the targeted therapy.

Investigation of the Compressibility and Compactibility of Titanate Nanotube-API Composites.

The present work aims to reveal the pharma-industrial benefits of the use of hydrothermally synthesised titanate nanotube (TNT) carriers in the manufacturing of nano-sized active pharmaceutical ingredients (APIs). Based on this purpose, the compressibility and compactibility of various APIs (diltiazem hydrochloride, diclofenac sodium, atenolol and hydrochlorothiazide) and their 1:1 composites formed with TNTs were investigated in a comparative study, using a Lloyd 6000R uniaxial press instrumented with a force gauge and a linear variable differential transformer extensometer. The tablet compression was performed without the use of any excipients, thus providing the precise energetic characterisation of the materials' behaviour under pressure. In addition to the powder functionality test, the post-compressional properties of the tablets were also determined and evaluated. The results of the energetic analysis demonstrated that the use of TNTs as drug carriers is beneficial in every step of the tabletting process: besides providing better flowability and more favourable particle rearrangement, it highly decreases the elastic recovery of the APIs and results in ideal plastic deformation. Moreover, the post-compressional properties of the TNT⁻API composites were found to be exceptional (e.g., great tablet hardness and tensile strength), affirming the above results and proving the potential in the use of TNT carriers for drug manufacturing.

Comparison of the properties of implantable matrices prepared from degradable and non-degradable polymers for bisphosphonate delivery.

The aim of the present study was the development of directly compressed tablets for implantable delivery of risedronate sodium for osteoporosis treatment and the comparison of the mechanism and kinetics of drug release from biogradable (chitosan) and non-degradable (PVC) polymer matrices. The compositions and process parameters were optimized in accordance to a mixed 2 and 3 level full factorial design. Critical Quality Attributes (CQA), such as diametral breaking hardness, porosity and speed of drug dissolution were investigated. The results revealed significant differences between the behaviours of the two polymers. Chitosan exhibited poor compressibility, which resulted in poor mechanical properties and the fast disintegration of chitosan based tablets. Nevertheless, despite the fast disintegration, the chitosan based matrices exhibited one-week-long continuous drug release, which can be due to a strong drug-carrier interaction. The presence of intermolecular hydrogen bonds was confirmed with FT-IR and NIR measurements. In contrast, PVC based compositions exhibited excellent compressibility, good tablet hardness and low porosity. The tablets remained intact during the dissolution and exhibited a slower release rate than what was measured in the case of chitosan based matrices. There was no sign of intermolecular association on NIR spectra, suggesting that the dissolution rate is basically determined by the porosity of tablets, but FT-IR measurements revealed some details of the molecular background of drug release mechanism.

Preparation and physicochemical characterization of matrix pellets containing APIs with different solubility via extrusion process.

In this study, a multiparticulate matrix system was produced, containing two different active pharmaceutical ingredients (APIs): enalapril-maleate and hydrochlorothiazide. The critical control points of the process were investigated by means of factorial design. Beside the generally used microcrystalline cellulose, ethylcellulose was used as matrix former to achieve modified drug release ensured by diffusion. The matrix pellets were made by extrusion-spheronization using a twin-screw extruder. Some pellet properties (aspect ratio, 10% interval fraction, hardness, deformation process) were determined. The aim of our study was to investigate how the two different APIs with different solubility and particle size influence the process. The amount of the granulation liquid plays a key role in the pellet shaping. A higher liquid feed rate is preferred in the pelletization process.

Physicochemical characterisation and investigation of the bonding mechanisms of API-titanate nanotube composites as new drug carrier systems.

Titanate nanotube (TNT) has recently been explored as a new carrier material for active pharmaceutical ingredients (API). The aim of the present work was to reveal the physicochemical properties of API-TNT composites, focusing on the interactions between the TNTs and the incorporated APIs. Drugs belonging to different Biopharmaceutical Classification System (BCS) classes were loaded into TNTs: diltiazem hydrochloride (BCS I.), diclofenac sodium (BCS II.), atenolol (BCS III.) and hydrochlorothiazide (BCS IV.). Experimental results demonstrated that it is feasible for spiral cross-sectioned titanate nanotubes to carry drugs and maintain their bioactivity. The structural properties of the composites were characterized by a range of analytical techniques, including FT-IR, DSC, TG-MS, etc. The interactions between APIs and TNTs were identified as electrostatic attractions, mainly dominated by hydrogen bonds. Based on the results, it can be stated that the strength of the association depends on the hydrogen donor strength of the API. The drug release of incorporated APIs was evaluated from compressed tablets and compared to that of pure APIs. Differences noticed in the dissolution profiles due to incorporation showed a correlation with the strength of interactions between the APIs and the TNTs observed in the above analytical studies.

Process analytical technology (PAT) approach to the formulation of thermosensitive protein-loaded pellets: Multi-point monitoring of temperature in a high-shear pelletization.

In the literature there are some publications about the effect of impeller and chopper speeds on product parameters. However, there is no information about the effect of temperature. Therefore our main aim was the investigation of elevated temperature and temperature distribution during pelletization in a high shear granulator according to process analytical technology. During our experimental work, pellets containing pepsin were formulated with a high-shear granulator. A specially designed chamber (Opulus Ltd.) was used for pelletization. This chamber contained four PyroButton-TH® sensors built in the wall and three PyroDiff® sensors 1, 2 and 3cm from the wall. The sensors were located in three different heights. The impeller and chopper speeds were set on the basis of 32factorial design. The temperature was measured continuously in 7 different points during pelletization and the results were compared with the temperature values measured by the thermal sensor of the high-shear granulator. The optimization parameters were enzyme activity, average size, breaking hardness, surface free energy and aspect ratio. One of the novelties was the application of the specially designed chamber (Opulus Ltd.) for monitoring the temperature continuously in 7 different points during high-shear granulation. The other novelty of this study was the evaluation of the effect of temperature on the properties of pellets containing protein during high-shear pelletization.

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 method's 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 method's usefulness in the analysis of intact dosage forms.

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.

Evaluation of the swelling behaviour of iota-carrageenan in monolithic matrix tablets.

The swelling properties of monolithic matrix tablets containing iota-carrageenan were studied at different pH values, with measurements of the swelling force and characterization of the profile of the swelling curve. The swelling force meter was linked to a PC by an RS232 cable and the measured data were evaluated with self-developed software. The monitor displayed the swelling force vs. time curve with the important parameters, which could be fitted with an Analysis menu. In the case of iota-carrageenan matrix tablets, it was concluded that the pH and the pressure did not influence the swelling process, and the first section of the swelling curve could be fitted by the Korsmeyer-Peppas equation.

Matrix tablets based on a carrageenan with the modified-release of sodium riboflavin 5'-phosphate.

The focus of this work was to produce modified-release monolithic matrix tablets containing sodium riboflavin 5'-phosphate (vitamin B2) as active pharmaceutical ingredient (API). Riboflavin 5'-phosphate is absorbed from the upper gastrointestinal tract by a specific transport mechanism. The aim of this work was the development of modified-release tablets from which most or the entire API can dissolve within 5 h. The dissolution was started in medium pH 1.2 (gastric juice) and finished in medium pH 4.5. The matrix former was iota-carrageenan combined with microcrystalline cellulose (MCC) and lactose in different ratios. Factorial design was used in this work so as to study the effects of the MCC/lactose ratio on the parameters of the tablets, and especially on the dissolution process. The dissolution data were subjected to statistical analysis, and the release profiles were fitted with different models. It was found that the MCC/lactose ratio influenced the quality of the tablets to a high degree. The Korsmeyer-Peppas model proved to characterize the total dissolution profile best, but fitting of the separate sections was also possible with a linear model.

Investigation of the cytotoxic effects of titanate nanotubes on Caco-2 cells.

Titanate nanotubes can be used as drug delivery systems, but limited information is available on their interactions with intestinal cells. In this study, we investigated the cytotoxicity and cellular uptake of titanate nanotubes on Caco-2 monolayers and found that up to 5 mg/ml concentration, these nanotubes are not cytotoxic and not able to permeate through the intestinal cell layer. Transmission electron microscopic experiments showed that titanate nanotubes are not taken up by cells, only caused a high-density granulation on the surface of the endoplasmic reticulum. According to these results, titanate nanotubes are suitable systems for intestinal drug delivery.

Preparing of pellets by extrusion/spheronization using different types of equipment and process conditions.

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.

Development of a Raman method to follow the evolution of coating thickness of pellets.

CONTEXT: 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. OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Modified-release capsules containing sodium riboflavin 5'-phosphate.

INTRODUCTION: The focus of this work was to produce delayed-release capsules containing riboflavin (vitamin B2, as API) layered pellets. Riboflavin therapy is indicated in patients with a riboflavin deficiency, which usually occurs in conjunction with malabsorption, alcoholism or a protein-calorie deficiency and rarely as the sole vitamin deficiency. Riboflavin is readily absorbed from the upper gastrointestinal tract by a specific transport mechanism. The dissolution rate of coated capsules was controlled through the coating of the capsules and the thickness of the coating layer. METHODS: The core pellets (Cellet 300) were loaded with a 10% aqueous solution of sodium riboflavin 5'-phosphate by a layering technique in a coating pan. Hard capsules were filled with riboflavin layered pellets and coated with Eudragit NE polymer with different coating layer thicknesses. The dissolution was tested in gastric and intestinal fluids with the half-change method. The dissolution profiles were analyzed with the use of different mathematical models and an attempt was made to predict the optimum coating film thickness that ensures the required degree and rate of dissolution. RESULTS: A new solid dosage form was developed which can enhance the bioavailability of riboflavin. RRSBW distribution and the Chapman-Richards growth function were used to fit the dissolution profiles. Statistical analysis indicated that the best products were described by the Chapman-Richards equation. The results were utilized to create a theoretical model suitable for prediction of the optimum film thickness that ensures the required release of riboflavin.

Elemental analysis of Ginkgo biloba leaf samples collected during one vegetation period.

The object of our work was the identification and quantification of inorganic elements in Ginkgo biloba L. leaves (Ginkgonis folium, Ginkgoaceae) by X-ray fluorescence analysis. The plant material was obtained from a 50-years-old female tree at the Comenius University Botanical Garden (Bratislava, Slovakia). Leaves were collected from early May to late September, with the last sample consisting of fallen leaves. The elements analyzed were: phosphorus, sulfur, potassium, calcium, scandium, iron, zinc, yttrium, molybdenum, tellurium, samarium, gadolinium, dysprosium, iridium, thallium and lead. The amounts of the monitored heavy metals were below the limits specified in Ph. Eur. 7 and PhS 1.

Application of physicochemical properties and process parameters in the development of a neural network model for prediction of tablet characteristics.

The importance of in silico modeling in the pharmaceutical industry is continuously increasing. The aim of the present study was the development of a neural network model for prediction of the postcompressional properties of scored tablets based on the application of existing data sets from our previous studies. Some important process parameters and physicochemical characteristics of the powder mixtures were used as training factors to achieve the best applicability in a wide range of possible compositions. The results demonstrated that, after some pre-processing of the factors, an appropriate prediction performance could be achieved. However, because of the poor extrapolation capacity, broadening of the training data range appears necessary.