Effect of crystal habit on the dissolution behaviour of simvastatin crystals and its relationship to crystallization solvent properties.

Simvastatin crystals, having same crystal structure but different types of habits and hence different intrinsic dissolution rate, were prepared by recrystallization from solvents selected according to their polarity index. Scanning electron microscopy, laser diffraction, image analysis, X-ray powder diffractometry, Fourier transform infrared spectroscopy and differential scanning calorimetry were used to investigate the physicochemical characteristics of the prepared crystals. The isolated crystals exhibited different crystal habits but possessed the same internal crystal structure. In this study the comparative intrinsic dissolution behaviour of the simvastatin crystals with different types of habits was studied and explained by surface energy and correlated to different solvent systems that were used for crystallization. In our work we diminished the influence of all other physical parameters that could influence the dissolution rate, e.g. particle size, specific surface area and polymorphism in order to focus the study onto the impact of crystal shape itself on the dissolution rate of simvastatin crystals. Rod shaped crystals isolated from more hydrophilic solvent mixture dissolved faster than plate-like crystals obtained from solvent mixture with lower polarity index. We correlated this fact to the different growth rate of the individual faces which resulted in different relative size of the individual crystal faces exposed to the dissolution medium as well as the chemical nature of those faces which in turn influenced the wettability and subsequent dissolution of the active pharmaceutical ingredient.

The effect of cores and coating dispersion composition on the mechanical and adhesion properties of hydroxypropyl methylcellulose films.

The influence of different additives on the mechanical properties of hydroxypropyl methylcellulose (HPMC) free films was studied using tensile testing. Free films were prepared using the cast method and sliced into bands, and their tensile strength and maximal elongation at break was measured. The results showed that the addition of PEG 400 and polysorbate 80 into the coating formulation had the most influence on the films' mechanical properties compared to the HPMC film used as a control. Tablet cores composed of microcrystalline cellulose and lactose with and without Mg stearate and compressed at three different compression forces were tested for wettability with coating formulations containing PEG 400 and polysorbate 80. For formulations with no Mg stearate added, the contact angle decreased with increasing core hardness and it also coincided with greater adhesion force of the coating. The addition of Mg stearate in the core led to reduced adhesion of the film coating with PEG 400, whereas the influence on the adhesion force of the film coating containing polysorbate 80 was negligible. The results also show that the adhesion force, regardless of the tablet core formulation, is highest at medium core hardness.

The influence of HPMC viscosity as FRC parameter on the release of low soluble drug from hydrophylic matrix tablets.

The importance of functionality-related characteristics (FRC) of hydroxypropyl methylcellulose (HPMC) described in the pharmacopeia monograph can be evaluated only for selected formulation or technological process. The aim of our work was to investigate the influence of apparent viscosity as one of the FRC for two batches of the same HPMC grade on the release properties of diclofenac sodium from HPMC matrix tablets. Our results show that two batches of HPMC differ in viscosity significantly and as a consequence, the significant differences were observed in the release profiles as well. HPMC-B sample has higher viscosity and therefore higher average molecular weight, thus the erosion and drug release were slower compared to HPMC-A sample with lower apparent viscosity. It can be concluded that batch-to-batch viscosity variation of the same HPMC grade can lead to the different release profiles; therefore the specification limits of some FRC should be postulated during the development of each individual formulation. However, the viscosity interval as FRC can not be generalized, because it is different for different tablet compositions.

Optimization of radial extrusion and pellet coating processes using PAT approaches.

FDA's initiative Pharmaceutical CGMPs for the 21st century opened the door for introduction of several risk based approaches in pharmaceutical industry. One significant advancement that has emerged is the implementation of process analytical technology (PAT), which has opened doors for understanding and controlling complex technological processes. Two such processes, radial extrusion and pellet coating, offer a solid foundation for the application of PAT tools due to their numerous critical process parameters. The aim of the first part of the study was to optimize the neutral pellet production to produce the pellets with properties desired for successful film coating using design of experiments (DoE). In the second part the optimized pellets underwent film coating and the coating quantity was predicted in real or near real-time using in-line and at-line NIR probes and the performance of both probes was compared. The desired properties of the pellets, narrow particle size distribution, high sphericity and high process yield, were successfully achieved. Models for film coating quantity prediction using in-line and at-line NIR probe were successfully calibrated and tested by coating two additional batches. Despite the limited sample size for model calibration, at-line NIR exhibited excellent prediction performance and enabled accurate determination of process end-point. The coating quantity determined by UV/VIS spectroscopy in both test batches deviated by less than 2.0 % from the target value. However, the in-line NIR probe, primarily due to its inferior spectral resolution, displayed a slightly lower quality of the calibrated model and notable overprediction for the tested batches.

Design of a drug delivery system with bimodal pH dependent release of a poorly soluble drug.

A delivery system which provides bimodal pH dependent release of poorly water soluble carvedilol in gastric and intestinal environment was designed. Preparation of solid dispersion with porous silica ensured a significantly higher dissolution rate of carvedilol in acidic and alkaline media in comparison to pure drug, while granulation of that solid dispersion with enteric polymer dispersion resulted in diminished immediate release in acidic media and fast release of the remaining drug in alkaline media. The ratio in quantities of first vs. second release was controlled with amount of enteric polymer dispersion used for granulation process. Desired 25 mg release of carvedilol at pH values 1.2 and 6.8 was achieved when 1.80 g of polymer per 1.0 g of solid dispersion (drug to silica ratio= 0.25 g : 2.0 g) was used.

Evaluation of solid carvedilol-loaded SMEDDS produced by the spray drying method and a study of related substances.

In this study, various formulations of solidified carvedilol-loaded SMEDDS with high SMEDDS loading (up to 67% w/w) were produced with the spray drying process using various porous silica-based carriers. The process yield was improved with higher atomization gas flow rate during the spray drying process and with prolonged mixing time of dispersion of liquid SMEDDS and solid porous carriers prior to the spray drying process. Depending on the choice of the carrier and the SMEDDS:carrier ratio in solid SMEDDS, different drug loading, self-microemulsifying properties, drug release rates, and released drug fractions were obtained. The products exhibited fast drug release due to preserved self-microemulsifying properties and the absence of crystalline carvedilol, which was confirmed with XRD and Raman mapping. A decrease in drug content during the stability study was observed and investigated. This was at least partially attributed to the chemical degradation of the drug. Key degradation products determined by the LC-MS method were amides formed by in situ reaction of carvedilol with fatty acids present in the oily phase of SMEDDS.

Interactions of biopolymers carrageenans with cationic drug doxazosin mesylate characterized by means of differential scanning calorimetry.

When ionic polymers (polyelectrolytes) are used as excipients in pharmaceutical formulations, the properties of oppositely charged drugs may be strongly affected by the charge-charge interactions or complex formation. Usually these effects are considered as a negative event resulting in a drug-excipient incompatibility. Sometimes ionic interactions are preferred to prolong drug release from dosage forms in a controllable manner. Ionic interactions of carrageenans with doxazosin mesylate were confirmed by differential scanning calorimetry (DSC). Evident peak shifts and shape changes of assumed desulfation peak of carrageenans in concordance with disappearance of melting peak of doxazosin mesylate (DM) in DSC curves were obtained. The range of thermal effects is depended on the ratio of doxazosin mesylate and carrageenans. The higher the ratio of DM compared to CARRs the more evident are the interactions.

Similarity of solid state structures of R- and S-isomers of clopidogrel hydrogensulphate salt.

The present study showed, that the crystal structures of R-isomer and the polymorphic form 1 of clopidrogrel hydrogensulphate S-isomer are very similar.

Solidification of carvedilol loaded SMEDDS by swirling fluidized bed pellet coating.

Self-(micro)emulsifying drug delivery systems (S(M)EDDS) have emerged as effective vehicles for enhancing bioavailability of poorly water soluble drugs, however solidification of the systems represents a major challenge. Objective of this study was development of carvedilol loaded liquid SMEDDS and transformation into solid pellets employing fluid-bed coating technologies. Carvedilol-loaded formulation of SMEDDS was comprised of Capmul® MCM EP, castor oil, Kolliphor® RH40 and PEG 400. The obtained liquid SMEDDS mixed with fillers and polymers was layered onto MCC pellets. Coating process was conducted in the modified, swirl-flow based fluid bed coating device, which was proved superior over the conventional Wurster fluid bed, with lower agglomeration rate. Use of polymer was essential for entrapping SMEDDS in the coating layer(s). Self-microemulsifying properties as well as fast drug release as one of main SMEDDS advantages were preserved in the solid products. Addition of lactose into the coating dispersion and applying intermediate and surface film coating to the pellets enabled higher drug loading and prevented sticking of the pellets during handling and storage. Present study indicates that the (swirling) fluid-bed pellet coating technology is a promising strategy for preparation of solid SMEDDS-coated pellets with adequate drug loading capacity and enhanced release of poorly water soluble drug.

Overview of solidification techniques for self-emulsifying drug delivery systems from industrial perspective.

Self-emulsifying drug delivery systems (SEDDS) are lipid formulations that improve solubility and oral bioavailability of the incorporated drug with poor biopharmaceutical properties. As liquids they are traditionally filled into soft or hard capsules. Transformation of SEDDS into solid dosage form has been extensively investigated in the recent years because solid dosage forms improve stability, handling and patient compliance. By using different solidification techniques selfemulsifying powders, granules, pellets and tablets can be produced. Appropriate excipients, solid carriers and processing parameters must be selected for each solidification technique to enable processability and preserve the self-emulsifying ability of the system upon its transformation into the solid formulation. In the present review various industrially applicable solidification techniques and excipients used for transforming liquid SEDDS into solid dosage forms with high production yield and good perspectives for being produced in large scales are discussed.

Application of experimental design methodology in development and optimization of drug release method.

The aim of our research was to apply experimental design methodology in the development and optimization of drug release methods. Diclofenac sodium (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid monosodium salt) was selected as a model drug and Naklofen retard prolonged release tablets, containing 100 mg of diclofenac sodium, were chosen as a model prolonged release system. On the basis of previous results, a three-level three-factorial Box-Behnken experimental design was used to characterize and optimize three physicochemical parameters, i.e. rotation speeds of the stirring elements, pH, and ionic strengths of the dissolution medium, affecting the release of diclofenac sodium from the tablets. The chosen dependent variables (responses) were a cumulative percentage of dissolved diclofenac sodium in 2, 6, 12 and 24 h. For estimation of coefficients in the approximating polynomial function, the least square regression method was applied. Afterwards, the information about the model reliability was verified by using the analysis of variance (ANOVA). The estimation of model factors' significance was performed by Student's t-test. For investigation of the shape of the predicted response surfaces and for model optimization, the canonical analysis was applied. Our study proved that experimental design methodology could efficiently be applied for characterization and optimization of analytical parameters affecting drug release and that it is an economical way of obtaining the maximum amount of information in a short period of time and with the fewest number of experiments.

Physical characterization of pantoprazole sodium hydrates.

Only two crystal forms of pantoprazole sodium, i.e. mono and sesquihydrate, were described in the literature. The objective of the present work was to study the polymorphisms and pseudopolymorphism of pantoprazole sodium and to characterize already known and new crystal forms. Two additional hydrate forms; i.e. form A, form B and amorphous form were obtained and further characterized by means of thermal analyses, X-ray powder diffraction (XRPD), mid-infrared spectroscopy (IR), near infrared spectroscopy (NIR), Raman spectroscopy, dynamic vapour sorption (DVS), true density, contact angle and solubility. From the results it can be concluded, that the most physically stable form of pantoprazole sodium is form B, whereas form A is the least stable form. Monohydrate and form A are not physically stable and convert into form B from saturated solution/suspension or at high relative humidity. Amorphous form can be obtained by conventional spray drying method or by distillation of solvent under reduced pressure.

Characterization of piroxicam crystal modifications.

Piroxicam polymorphism was extensively studied in the past. The objective of the present work was to evaluate polymorphism of piroxicam once again and to characterize the obtained crystal forms. Three polymorphic forms and one monohydrate form were obtained by crystallization from saturated solutions in various solvents. Polarity of solvents and crystallization rate defined by temperature of crystallization were found to be critical parameters in determining the polymorphic form. A new polymorphic form designated as form III was obtained by forced crystallization using dry ice. Only form I with the highest melting point was found to be stable under mechanical and thermal stress. Differences in IR spectra were attributed mainly to the differences in number and positions of H-bonds in the piroxicam crystal forms. Slow crystallization of piroxicam from absolute ethanol solution resulted in a mixture of form II and monohydrate. Crystal structure analysis proved that form II represents form alpha(2) already proposed in the literature. Differences in dissolution rates among crystal forms of piroxicam were attributed to differences in their wettability, where highest wettability was obtained for monohydrate and the lowest for form III.

Statistical optimisation of diclofenac sustained release pellets coated with polymethacrylic films.

The objective of the present study was to evaluate three formulation parameters for the application of polymethacrylic films from aqueous dispersions in order to obtain multiparticulate sustained release of diclofenac sodium. Film coating of pellet cores was performed in a laboratory fluid bed apparatus. The chosen independent variables, i.e. the concentration of plasticizer (triethyl citrate), methacrylate polymers ratio (Eudragit RS:Eudragit RL) and the quantity of coating dispersion were optimised with a three-factor, three-level Box-Behnken design. The chosen dependent variables were cumulative percentage values of diclofenac dissolved in 3, 4 and 6 h. Based on the experimental design, different diclofenac release profiles were obtained. Response surface plots were used to relate the dependent and the independent variables. The optimisation procedure generated an optimum of 40% release in 3 h. The levels of plasticizer concentration, quantity of coating dispersion and polymer to polymer ratio (Eudragit RS:Eudragit RL) were 25% w/w, 400 g and 3/1, respectively. The optimised formulation prepared according to computer-determined levels provided a release profile, which was close to the predicted values. We also studied thermal and surface characteristics of the polymethacrylic films to understand the influence of plasticizer concentration on the drug release from the pellets.

Investigation of polymeric nanoparticles as carriers of enalaprilat for oral administration.

Enalaprilat is a typical angiotensin-converting enzyme inhibitor and is very poorly absorbed from the gastrointestinal tract. The aim of this study was to design and characterize poly-(lactide-co-glycolide) (PLGA) and polymethylmethacrylate (PMMA) nanoparticles containing enalaprilat and to evaluate the potential of these colloidal carriers for the transport of drugs through the intestinal mucosa. Nanoparticle dispersions were prepared by the emulsification-diffusion method and characterized according to particle size, zeta potential, entrapment efficiency and physical stability. Effective permeabilities through rat jejunum of enalaprilat in solution and in enalaprilat-loaded nanoparticles were compared using side-by-side diffusion chambers. The solubility of enalaprilat is very low in many acceptable organic solvents, but in benzyl alcohol is sufficient to enable the production of nanoparticles by the emulsification-diffusion process. The diameters of drug-loaded PMMA and PLGA nanoparticles were 297 and 204 nm, respectively. The concentration of the stabilizer polyvinyl alcohol (PVA) in dispersion has an influence on particle size but not on drug entrapment. The type of polymer has a decisive influence on drug content--7 and 13% for PMMA and PLGA nanoparticles, respectively. In vitro release studies show a biphasic release of enalaprilat from nanoparticle dispersions-fast in the first step and very slow in the second. The apparent permeability coefficient across rat jejunum of enalaprilat entrapped in PLGA nanoparticles is not significantly improved compared with enalaprilat in solution.

Optimisation of floating matrix tablets and evaluation of their gastric residence time.

The present investigation concerns the development of the floating matrix tablets, which after oral administration are designed to prolong the gastric residence time, increase the drug bioavailability and diminish the side effects of irritating drugs. The importance of the composition optimisation, the technological process development for the preparation of the floating tablets with a high dose of freely soluble drug and characterisation of those tablets (crushing force, floating properties in vitro and in vivo, drug release) was examined. Tablets containing hydroxypropyl methylcellulose (HPMC), drug and different additives were compressed. The investigation shows that tablet composition and mechanical strength have the greatest influence on the floating properties and drug release. With the incorporation of a gas-generating agent together with microcrystalline cellulose, besides optimum floating (floating lag time, 30 s; duration of floating, >8 h), the drug content was also increased. The drug release from those tablets was sufficiently sustained (more than 8 h) and non-Fickian transport of the drug from tablets was confirmed. Radiological evidence suggests that, that the formulated tablets did not adhere to the stomach mucus and that the mean gastric residence time was prolonged (>4 h).

Oxidation of lovastatin in the solid state and its stabilization with natural antioxidants.

Oxidative instability of the hydroxy methylglutaryl Co-A reductase inhibitor lovastatin in the solid state and stabilization with natural antioxidants (ascorbic acid, rutin, gallic acid, quercetin and caffeic acid) was investigated. Lovastatin in the solid state and binary mixtures with 10% (w/w), 25% (n/n), 12.5% (n/n) and 6.3% (n/n) of each of the antioxidants were prepared. Oxidation experiments were performed on the scanning calorimeter using dynamic oxygen atmosphere. The amount of non-oxidized lovastatin was determined using HPLC. The results of the experiments have shown that lovastatin is unstable to oxidation under higher temperatures and in the presence of oxygen, and that some antioxidants markedly stabilize the drug. The most significant antioxidative effect was seen with caffeic acid and rutin, followed by gallic acid and quercetin. Ascorbic acid was only moderately effective. The results prove that flavonoids do have significant antioxidative potential. This phenomenon can be used to improve oxidative stability of drugs such as lovastatin which are sensitive to the presence of oxygen.

Development and optimization of the drug release determination of iron from iron prolonged release tablets.

The aim of this research was to develop and optimize the drug release determination of iron from iron prolonged release tablets. First, solubility characteristics of ferrous sulfate in different aqueous media with a pH in the range of 1 to 8 were studied. According to the results obtained different physicochemical conditions that influence drug release of iron from iron prolonged release tablets were checked. Various aqueous media with a pH in the range of 1 to 7.4, different volumes of dissolution media, various rotation speeds of stirring elements, different dissolution apparatus (apparatus 1/basket apparatus and apparatus 2/paddle apparatus according to USP/Ph. Eur.) were verified. For evaluation of dissolved iron two different methods were checked: atomic absorption spectrometry and redox titration. Redox titration was proved to be a reproducible, discriminatory, selective and cost effective method for evaluation of dissolved iron from iron prolonged release tablets and can be applied in the quality control of solid dosage forms containing iron compounds.

Prediction of the in vivo performance of enteric coated pellets in the fasted state under selected biorelevant dissolution conditions.

The purpose of this research was to predict the in vivo dissolution of lansoprazole from enteric coated pellets in the fasted state using a biorelevant flow-through dissolution method with low flow rates and volumes close to those in vivo. Additionally, a novel rotating stirring element, composed from magnet inserted in a silicone tube, was used to produce the movement of the pellets and expose them to slightly increased physical stress. Obtained dissolution results were compared to the dissolution results of our previous work using the USP IV with higher flow rate (11 ml/min). As drug release from enteric coated pellets usually starts in the small intestine, the influence of pellets' residence time in the gastric medium and additionally the effect of different media on drug release was studied. Prolongation of residence time in an acidic medium had only minor effect on the release rate after initial lag time, but significantly reduced the total amount of the drug released from both tested formulations, which was attributed to the drug's degradation in an acidic medium. The increased physical load on the pellets induced by the rotating stirring element compensated for the decrease of flow rate from 11 ml/min using the USP IV to 3 ml/min using the non-compendial system. Considering also gastric emptying kinetics good prediction of the in vivo release was achieved compared to in vivo absorption data obtained from a pharmacokinetic study under fasting conditions. Thus, using more physiologically relevant dissolution conditions, expressed through low volume and lower flow rate, and in combination with increased mechanical stress we obtained equally good in vitro/in vivo correlation as using USP IV and higher flow rates. Comparison of the dissolution results obtained with two different systems provided additional insight into product behaviour and improved prediction of in vivo performance.

Characterization of physicochemical properties of hydroxypropyl methylcellulose (HPMC) type 2208 and their influence on prolonged drug release from matrix tablets.

The key physicochemical properties of functional excipients should be identified, and the influence of their variability on the properties of the final dosage form should be evaluated during the development phase. Excipients produced by different manufacturers and/or by different manufacturing processes should have comparable properties. Hydroxypropyl methylcellulose (HPMC) with a high molecular weight is a functional excipient often used in solid matrix systems with prolonged release of active pharmaceutical ingredients (API). This study investigates whether HPMC manufactured by two manufacturers using different chemical procedures differs in particle-size distribution, particle shape, particle morphology, chemical composition, and dissolution of diclofenac sodium as a model drug. NIR spectroscopy was introduced and calibration models were developed to detect physical differences among HPMC batches from two different origins. The physical differences between HPMC samples were additionally confirmed with scanning electron microscopy (SEM), gas chromatography (GC) measurements, and dissolution testing of hydrophilic matrix tablets. Our results prove that, even if HPMC polymers manufactured from two different sources comply with the pharmacopeial specification, they significantly differ in physicochemical properties and thus influence the properties of the formulated dosage forms.