Panagiotis Barmpalexis

Solid dispersions in the development of a nimodipine floating tablet formulation and optimization by artificial neural networks and genetic programming

The present study investigates the use of nimodipine-polyethylene glycol solid dispersions for the development of effervescent controlled release floating tablet formulations. The physical state of the dispersed nimodipine in the polymer matrix was characterized by differential scanning calorimetry, powder X-ray diffraction, FT-IR spectroscopy and polarized light microscopy, and the mixture proportions of polyethylene glycol (PEG), polyvinyl-pyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), effervescent agents (EFF) and nimodipine were optimized in relation to drug release (% release at 60 min, and time at which the 90% of the drug was dissolved) and floating properties (tablets floating strength and duration), employing a 25-run D-optimal mixture design combined with artificial neural networks (ANNs) and genetic programming (GP). It was found that nimodipine exists as mod I microcrystals in the solid dispersions and is stable for at least a three-month period. The tablets showed good floating properties and controlled release profiles, with drug release proceeding via the concomitant operation of swelling and erosion of the polymer matrix. ANNs and GP both proved to be efficient tools in the optimization of the tablet formulation, and the global optimum formulation suggested by the GP equations consisted of PEG=9%, PVP=30%, HPMC=36%, EFF=11%, nimodipine=14%.

Optimizing the ability of PVP/PEG mixtures to be used as appropriate carriers for the preparation of drug solid dispersions by melt mixing technique using artificial neural networks: I

In the present study, the efficiency of PVP/PEG200 mixtures as appropriate carries for the preparation of solid dispersions by melt mixing was evaluated. Felodipine (FELO) was used as a poorly water soluble model drug. The effect of several melt mixing parameters, (PVP/PEG ratio, time and temperature of melt mixing, and drug content), on the physical state of FELO and the dissolution characteristics of the dispersions were investigated. DSC, XRD, and SEM analysis revealed that in all cases, amorphous drug nanodispersions were prepared. This was attributed to the increased miscibility of the PVP-FELO system, induced by the presence of PEG200, which acted as plasticizer. FT-IR analysis showed hydrogen bonding between FELO (NH) and the PVP carrier (CO). The release rate of the drug depends mainly on the drug content and is higher in solid dispersions with low drug content and ratio of carrier to plasticizer (PVP/PEG200). The melt mixing variations (time and temperature of mixing) had lower impact on FELO release rate. Finally, artificial neural networks, used to correlate the examined formulation and process variables of hot melt mixing with dissolution parameters, showed good prediction ability.

Developing and optimizing a validated isocratic reversed-phase high-performance liquid chromatography separation of nimodipine and impurities in tablets using experimental design methodology.

In the present study an isocratic reversed-phase high-performance liquid chromatography was investigated for the separation of nimodipine and impurities (A, B and C) using statistical experimental design. Initially, a full factorial design was used in order to screen five independent factors: type of the organic modifier - methanol or acetonitrile - and concentration, column temperature, mobile phase flow rate and pH. Except pH, the rest examined factors were identified as significant, using ANOVA analysis. The optimum conditions of separation (optimum values of significant factors) determined with the aid of central composite design were: (1) mobile phase: acetonitrile/H(2)O (67.5/32.5, v/v), (2) column temperature 40 degrees C and (3) mobile phase flow rate 0.9 ml/min. The proposed method showed good prediction ability (observed-predicted correlation). The analysis was found to be linear, specific, precise, sensitive and accurate. The method was also studied for robustness and intermediate precision using experimental design methodology. Three commercially available nimodipine tablets were analyzed showing good % recovery and %RSD. No traceable amounts of impurities were found in all products.

The Influence of Surfactant HLB and Oil/Surfactant Ratio on the Formation and Properties of Self-emulsifying Pellets and Microemulsion Reconstitution

Self-emulsifying oil/surfactant mixtures can be incorporated into pellets that have the advantages of the oral administration of both microemulsions and a multiple-unit dosage form. The purpose of this work was to study the effects of surfactant hydrophilic–lipophilic balance (HLB) and oil/surfactant ratio on the formation and properties of self-emulsifying microcrystalline cellulose (MCC) pellets and microemulsion reconstitution. Triglycerides (C8–C10) was the oil and Cremophor ELP and RH grades and Solutol the surfactants. Pellets were prepared by extrusion/spheronization using microemulsions with fixed oil/surfactant content but with different water proportions to optimize size and shape parameters. Microemulsion reconstitution from pellets suspended in water was evaluated by turbidimetry and light scattering size analysis, and H-bonding interactions of surfactant with MCC from FT-IR spectra. It was found that water requirements for pelletization increased linearly with increasing HLB. Crushing load decreased and deformability increased with increasing oil/surfactant ratio. Incorporation of higher HLB surfactants enhanced H-bonding and resulted in faster and more extensive disintegration of MCC as fibrils. Reconstitution was greater at high oil/surfactant ratios and the droplet size of the reconstituted microemulsions was similar to that in the wetting microemulsions. The less hydrophilic ELP with a double bond in the fatty acid showed weaker H-bonding and greater microemulsion reconstitution. Purified ELP gave greater reconstitution than the unpurified grade. Thus, the work demonstrates that the choice of type and quantity of the surfactant used in the formulation of microemulsions containing pellets has an important influence on their production and performance.

Dissolution rate and stability study of flavanone aglycones, naringenin and hesperetin, by drug delivery systems based on polyvinylpyrrolidone (PVP) nanodispersions

Objective: To study the dissolution behavior, the release mechanism and the stability of nanodispersion system of aglycones with PVP. Methods: The nanodispersion system of polyvinylpyrrolidone (PVP)/naringenin–hesperetin was prepared using the solvent evaporation method. The chemical stability (compatibility) of naringenin and hesperetin in the prepared dispersions was studied under accelerated conditions for 3 months. The evaluation of physical stability was performed by X-ray diffraction analysis (XRD) and by comparing the dissolution profile before and after storage at high temperature and moisture (40ºC, RH 75%). Results: The dissolution rate of naringenin and hesperetin released was dramatically increased in the nanodispersion system of PVP/naringenin–hesperetin (80/20, w/w). The release mechanism of both flavanone aglycones was better described by the diffusion model (Higuchi model). Also it was found that the rate-limiting step that controlled the release of naringenin and hesperetin in the nanodispersion system was dissolution of the carrier (PVP). Conclusions: During accelerated degradation analysis, for 3 months at high temperature and moisture, PVP nanodispersion system showed enhanced chemical compatibility and physical stability. The physical evaluation (obtained from XRD analysis) of PVP/naringenin–hesperetin (80/20, w/w) in the selected storage conditions did not show any crystallization of flavanone aglycones in the PVP nanodispersion system or any change in their release profile.

Development of PVP/PEG mixtures as appropriate carriers for the preparation of drug solid dispersions by melt mixing technique and optimization of dissolution using artificial neural networks

The effect of plasticizers (PEG) molecular weight (MW) on PVP based solid dispersions (SDs), prepared by melt mixing, was evaluated in the present study using Tibolone as a poorly water soluble model drug. PEGs with MW of 400, 600, and 2000 g/mol were tested, and the effect of drug content, time and temperature of melt mixing on the physical state of Tibolone, and the dissolution characteristics from SDs was investigated. PVP blends with PEG400 and PEG600 were completely miscible, while blends were heterogeneous. Furthermore, a single Tg recorded in all samples, indicating that Tibolone was dispersed in a molecular lever (or in the form of nanodispersions), varied with varying PEGs molecular weight, melt mixing temperature, and drug content, while FTIR analysis indicated significant interactions between Tibolone and PVP/PEG matrices. All prepared solid dispersion showed long-term physical stability (18 months in room temperature). The extent of interaction between mixture components was verified using Fox and Gordon-Taylor equations. Artificial neural networks, used to correlate the studied factors with selected dissolution characteristics, showed good prediction ability.

Artificial neural networks in the optimization of a nimodipine controlled release tablet formulation

Artificial neural networks (ANNs) were employed in the optimization of a nimodipine zero-order release matrix tablet formulation, and their efficiency was compared to that of multiple linear regression (MLR) on an external validation set. The amounts of PEG-4000, PVP K30, HPMC K100 and HPMC E50LV were used as independent variables following a statistical experimental design, and three dissolution parameters (time at which the 90% of the drug was dissolved, t(90%), percentage of nimodipine released in 2 and 8h, Y(2h), and Y(8h), respectively) were chosen as response variables. It was found that a feed-forward back-propagation ANN with eight hidden units showed better fit for all responses (R(2) of 0.96, 0.90 and 0.98 for t(90%), Y(2h) and Y(8h), respectively) compared to the MLR models (0.92, 0.87 and 0.92 for t(90%), Y(2h) and Y(8h), respectively). The ANN was further simplified by pruning, which preserved only PEG-4000 and HPMC K100 as inputs. Optimal formulations based on ANN and MLR predictions were identified by minimizing the standardized Euclidian distance between measured and theoretical (zero order) release parameters. The estimation of the similarity factor, f(2), confirmed ANNs increased prediction efficiency (81.98 and 79.46 for the original and pruned ANN, respectively, and 76.25 for the MLR).

Controlled release formulations of risperidone antipsychotic drug in novel aliphatic polyester carriers: Data analysis and modelling

In the present study a series of biodegradable and biocompatible poly(ε-caprolactone)/poly(propylene glutarate) (PCL/PPGlu) polymer blends were investigated as controlled release carriers of Risperidone drug (RISP), appropriate for transdermal drug delivery. The PCL/PPGlu carriers were prepared in different weight ratios. Miscibility studies of blends were evaluated through differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). Hydrolysis studies were performed at 37°C using a phosphate buffered saline solution. The prepared blends have been used for the preparation of RISP patches via solvent evaporation method, containing 5, 10 and 15wt% RISP. These formulations were characterized using FT-IR spectroscopy, DSC and WAXD in order to evaluate interactions taking place between polymer matrix and drug, as well as the dispersion and the physical state of the drug inside the polymer matrix. In vitro drug release studies were performed using as dissolution medium phosphate buffered saline simulating body fluids. It was found that in all cases controlled release formulations were obtained, while the RISP release varies due to the properties of the used polymer blend and the different levels of drug loading. Artificial Neural Networks (ANNs) were used for dissolution behaviour modelling showing increased correlation efficacy compared to Multi-Linear-Regression (MLR).

Melt extrusion process for adjusting drug release of poorly water soluble drug felodipine using different polymer matrices

Abstract The purpose of the present study was to use commercial available polymers like PVP/PEG, soluplus® and kollidon® SR to prepare immediate and sustained release formulations of felodipine by hot melt mixing method. Solid dispersions containing 5, 10, 20 and 30 wt% drug have been prepared in a Haake‐Buchler Reomixer at melt temperature 130 °C and mixing time 10 min. As was found from DSC and XDR studies completely amorphous and miscible solid dispersions can be prepared. In all cases a single glass transition was recorded, which is depended from the used drug amount. Hydrogen bonds and the molecular interaction between felodipine and polymer matrices are responsible for the miscibility of prepared formulations. This has as result the substantial enhancement of felodipine release rate in PVP/PEG mixture and due to the high solubility of used polymers immediate release formulations have been prepared. On the contrary, sustained release formulations can be prepared in the case of kollidon SR solid dispersions. The release mechanism of all preparations was studied using different kinetic models. Finally, binding affinity values calculated by molecular docking simulations were used as estimators for predicting long‐term drugs physical stability in solid dispersions. Graphical abstract Figure. No caption available.

Physicochemical characterization of nimodipine–polyethylene glycol solid dispersion systems

Abstract This study investigates the solid–solid interactions between nimodipine (NIM) and polyethylene glycol (PEG) of different mean molecular weights (PEG 2000, 4000 and 6000), in solid dispersion systems, applying differential scanning calorimetry (DSC), Fourier-Transform infrared spectroscopy, powder X-ray diffraction (PXRD), hot stage microscopy (HSM) and theoretical modeling by the Flory–Huggins (FH) solution theory. Phase diagrams constructed with the aid of DSC and FH solution theory showed sensitivity on the estimated values of the FH interaction parameter (χ). When χ is considered a constant number (χ = α, α ≠ 0), formation of a eutectic mixture is predicted in the 70–80% w/w PEG concentration region, while when χ was considered as a function of concentration and temperature (χ = f(φ,Τ)), the model predicts the formation of monotectic systems. Construction of more precise phase diagrams by HSM to the aid of Kofler’s “contact preparation” method confirmed the monotectic nature of the examined systems. Studies on NIM’s re-crystallization process in the solid dispersions revealed a strong dependence of the crystallization rate, as well as the resulting crystal form, on the mean molecular weight and concentration of PEG: NIM crystallization rates decrease as PEG’s MW increases, while NIM mod II crystals predominate in dispersions prepared at temperatures above NIM’s liquidus and growth of NIM mod I prevailing in PEG-rich samples.