Process analytical technology tools for process control of roller compaction in solid pharmaceuticals manufacturing

This article presents an overview of using process analytical technology in monitoring the roller compaction process. In the past two decades, near-infrared spectroscopy, near-infrared spectroscopy coupled with chemical imaging, microwave resonance technology, thermal effusivity and various particle imaging techniques have been used for developing at-, off-, on- and in-line models for predicting critical quality attributes of ribbons and subsequent granules and tablets. The common goal of all these methods is improved process understanding and process control, and thus improved production of high-quality products. This article reviews the work of several researchers in this field, comparing and critically evaluating their achievements

Lipid-based systems as promising approach for enhancing the bioavailability of poorly water-soluble drugs

Low oral bioavailability as a consequence of low water solubility of drugs is a growing challenge to the development of new pharmaceutical products. One of the most popular approaches of oral bioavailability and solubility enhancement is the utilization of lipid-based drug delivery systems. Their use in product development is growing due to the versatility of pharmaceutical lipid excipients and drug formulations, and their compatibility with liquid, semi-solid, and solid dosage forms. Lipid formulations, such as self-emulsifying (SEDDS), self-microemulsifying SMEDDS) and self-nanoemulsifying drug delivery systems (SNEDDS) were explored in many studies as an efficient approach for improving the bioavailability and dissolution rate of poorly water-soluble drugs. One of the greatest advantages of incorporating poorly soluble drugs into such formulations is their spontaneous emulsification and formation of an emulsion, microemulsion or nanoemusion in aqueous media. This review article focuses on the following topics. First, it presents a classification overview of lipid-based drug delivery systems and mechanisms involved in improving the solubility and bioavailability of poorly water-soluble drugs. Second, the article reviews components of lipid-based drug delivery systems for oral use with their characteristics. Third, it brings a detailed description of SEDDS, SMEDDS and SNEDDS, which are very often misused in literature, with special emphasis on the comparison between microemulsions and nanoemulsions

Investigation of design space for freeze-drying injectable ibuprofen using response surface methodology

This study explores the use of a statistical model to build a design space for freeze-drying two formulations with ibuprofen. A 2 × 3 factorial experimental design was used to evaluate independent variables (filling volume and annealing time) and responses as residual moisture content, specific surface area and reconstitution time. A statistical model and response surface plots were generated to define the interactions among the selected variables. The models constructed for both formulations suggest that 1 ml of filled volume and no annealing should be used to achieve optimal residual moisture content, specific surface area and reconstitution time. The proposed models were validated with additional experiments, in which the responses observed were mainly in close agreement with the predicted ones. Additionally, the established models demonstrate the reliability of the evaluation procedure in predicting the selected responses

Comparison of CE and HPLC Methods for Determining Lovastatin and Its Oxidation Products after Exposure to an Oxidative Atmosphere

Lovastatin is a cholesterol-lowering agent, which competitively inhibits the enzyme HMG-CoA reductase. Several HPLC methods for its analysis have been developed but there is no report of its determination using capillary electrophoresis (CE). In this paper, we report the development of a simple CE method for lovastatin determination, which is selective with respect to its degradation products and useful for routine analyses. Since the molecule of lovastatin in its lactone form is uncharged and is only slightly soluble in water, base hydrolysis was used to open the lactone ring and transform the compound into a water-soluble acid form, which is negatively charged. Different solvents, different amounts of NaOH added, different hydrolysis times and different temperatures for sample preparation were tested. The CE and HPLC methods are compared in terms of susceptibility, precision, linearity and accuracy. HPLC method was found to be more susceptible and more precise

Uporaba metodologije odgovornih površin za študij in situ granulacije s talinami v zvrtinčenih plasteh

The objective of this work was to investigate the influence of selected individual variables (binder content, inlet air temperature, and product endpoint temperature) of in situ fluid bed melt granulation on the granule particle size distribution and percentage of dissolved carvedilol using a three-factor, five-level circumscribed central composite design. Increased binder content had the effect of increasing the granule particle size and drug dissolution rate. The effect of inlet air temperature and product endpoint temperature was found to be more pronounced in case of granule particle size parameters. Within the studied intervals, the optimal quantity of binder as well as optimal process parameters were identified and validated using response surface methodology. Utilizing these optimal process and formulation parameters, successful scaling up of the fluid bed melt granulation process was carried out. Granule characteristics obtained at pilot scale are comparable to those obtained at laboratory scale.V raziskovalnem delu smo z uporabo tri-faktorskega pet-nivojskega središčnega mešanega eksperimentalnega načrta proučevali vpliv izbranih procesnih spremenljivk (delež veziva, temperatura vhodnega zraka in končna temperatura produkta) in situ granulacije s talinami na porazdelitev velikosti izdelanih granul in na delež raztopljenega karvedilola. Ugotovili smo, da povečana količina veziva v formulaciji kaže učinek povečanja velikosti izdelanih granul kakor tudi hitrosti raztapljanja karvedilola. Prav tako smo ugotovili, da temperatura vhodnega zraka in končna temperatura produkta izkazujeta izrazit vpliv na parametre velikosti granul. Z metodo odgovornih površin smo znotraj proučevanih intervalov določili in validirali optimalno količino veziva in optimalne procesne parametre. Z uporabo optimalnih formulacijskih in procesnih parametrov smo tehnologijo in situ granulacije s talinami uspešno prenesli iz laboratorijskega v večje (pilotno) merilo, pri čemer smo zagotovili primerljivost proučevanih lastnosti granulata

Solubilization of ibuprofen for freeze dried parenteral dosage forms

Ibuprofen, a weakly acidic non-steroidal anti-inflammatory drug having poor aqueous solubility, is a challenging drug for the development of pharmaceutical formulations, resulting in numerous research attempts focusing on improvement of its solubility and consequently bioavailability. Most studies have been done for solid dosage forms, with very little attention paid to parenterals. Hence, the main purpose of the present study was to enhance ibuprofen solubility as a result of formulation composition and the freeze drying process. Moreover, the purpose was to prepare a freeze dried dosage form with improved ibuprofen solubility that could, after simple reconstitution with water for injection, result in an isotonic parenteral solution. Solubility of ibuprofen was modified by various excipients suitable for parenteral application. Drug interactions with selected excipients in the final product/lyophilisate were studied by a combined use of XRPD, DSC, Raman and ssNMR. Analyses of lyophilized samples showed solubility enhancement of ibuprofen and in situ formation of an ibuprofen salt with the alkaline excipients used

Sferična kristalizacija zdravilnih učinkovin

Spherical crystallization of drugs is the process of obtaining larger particles by agglomeration during crystallization. The most common techniques used to obtain such particles are spherical agglomeration and quasi-emulsion solvent diffusion. Ammonia diffusion systems and crystallo-co-agglomeration are extensions of these techniques. By controlling process parameters during crystallization, such as temperature, stirring rate, type and amount of solvents, or excipient selection, it is possible to control the formation of agglomerates and obtain spherical particles of the desired size, porosity, or hardness. Researchers have reported that the particles produced have improved micromeritic, physical, and mechanical properties, which make them suitable for direct compression. In some cases, when additional excipients are incorporated during spherical crystallization, biopharmaceutical parameters including the bioavailability of drugs can also be tailored.Sferična kristalizacija je postopek izdelave večjih delcev z aglomeracijo manjših med samo kristalizacijo. Najpogosteje uporabljeni tehniki za izdelavo takšnih delcev sta sferična aglomeracija in kvaziemulzija z difuzijo topila. Sistem z difuzijo amoniaka in kristalo-ko-aglomeracija sta razširitvi teh dveh metod. Z nadzorovanjem procesnih parametrov med kristalizacijo, kot sta temperatura in hitrost mešanja, z izbiro lastnosti in množine topil ter z izbiro pomožnih snovi, lahko vplivamo na nastanek aglomeratov in izdelamo sferične delce želenih velikosti, primerne poroznosti ali trdote. Raziskovalci poročajo, da imajo izdelani delci izboljšane pretočne lastnosti, izboljšane druge fizikalne in mehanske lastnosti zaradi česar so primerni za direktno tabletiranje. V nekaterih primerih lahko ob vgradnji ustreznih pomožnih snovi, ki jih dodamo med procesom sferične kristalizacije, izboljšamo tudi biofarmacevtske lastnosti zdravilnih učinkovin vključno s povečanjem biološke uporabnosti

Model od strategic determination of tool distribution based on the fuzzy rules

Cilj, ki ga želimo izpostaviti v prispevku, je izdelava modela mehke logike, s katerim simuliramo dinamični sistem distribucije orodij. Narejen je model gibanja orodij v proizvodnem procesu in skladišču srednje velikega podjetja. V podjetju je prilagodljivost proizvodnje v veliki meri odvisna od obsega zelo kakovostnih izdelkov, dobrega nadzora pretoka in strateške distribucije orodij, ki morajo biti na voljo vedno ob pravem času in v zadostnih količinah. Imamo dinamični pretok orodij, ki ga je mogoče nadzorovati z uporabo zakonov mehke logike in povratnih signalov. Z njimi primerjamo željene in dobljene vrednosti in krmilimo pretok. V prispevku je prikazan model, s katerim smo prikazali časovne odmike, ki nastanejo pri distribuciji orodij. Predstavljeni realni nadzorni sistem pretoka orodij v podjetju je sestavljen iz pretoka materiala, informacij in proizvodnih sredstev. V sistemu obstajajo zveze med posameznimi enotami podjetja, ki so povezana z informacijskimi tokovi, s katerimi smo povečali prilagodljivost sistema.This paper concerns the working out of a fuzzy algorithm model to simulate the dynamic system of tool distribution. A model of tool motion in the production process and in the store of a medium-size company is made. In a company, the production flexibility depends to a large extent on the high-quality manufacturing and the flow and the strategic distribution of tools, which must always be available in time and in sufficient quantities. Tool flow is dynamical and can be monitored according to fuzzy algorithm principles by means of feedback signals with which the desired and obtained values are compared and the flow controlled. This paper shows the model with which we presented the time delays occuring during the tool distribution. The presented real tool distribution monitoring system of a company comprises the flow of materials, informations and production means. The system features the interconnections between the individual units of the company, involved in the information flows with which the flexibility of the system was increased

Študij kompresibilnosti in kompaktibilnosti realne zmesi za tabletiranje: Vpliv velikosti granulata

This study investigates the effect of particle size on the compression characteristics of wet- (fluid-bed granulation – FBG) and dry-granulated (slugging – DGS) tableting mixtures. Particle-size distribution, flowability, compressibility, using the Heckel and Walker model, compactibility and elastic recovery as well as friability and disintegration were determined and compared between the two particle size fractions (180400 µm, 400710 µm) and initial unsieved mixtures. The results showed that the particle size of granules had no effect on the compressibility of the FBG and DGS mixtures, due to the high fragmenting nature of the formulation used in this study. On the other hand, compactibility was particle size dependent, as larger-sized fractions showed higher crushing strength, lower friability, and lower elastic recovery. This was attributed to increased fragmentation of larger particles, allowing stronger bonding between uncontaminated surface areas. As a result of better rearrangement of particles, both initial tableting mixtures showed lower compressibility and lower compactibility compared to their sieved fractions.V študiji smo proučevali vpliv velikosti delcev na stisljivost vlažno (vrtinčnoslojno granuliranje- FBG) in suho (briketiranje- DGS) granuliranih zmesi za tabletiranje. Dvema velikostnima frakcijama vsake zmesi (180-400 µm, 400-710 µm) in primerjalno nepresejanima zmesema smo določili porazdelitev velikosti delcev, pretočnost, kompresibilnost z uporabo Heckelovega in Walkerjevega modela in kompaktibilnost. Tabletam izdelanim iz posameznih zmesi smo določili delež elastične relaksacije, krušljivost in razpadnost. Rezultati naše študije potrjujejo, da velikost granulata ne vpliva na kompresibilnost FBG in DGS zmesi za tabletiranje, kar je posledica izrazite fragmentacijske narave uporabljene formulacije zmesi. V nasprotju s tem dejstvom pa je bil potrjen signifikanten vpliv velikosti delcev na kompaktibilnost, saj so imele tablete izdelane iz večjih velikostnih frakcij višjo natezno trdnost, nižjo krušljivost in nižji delež elastične relaksacije. To pripisujemo izrazitejši fregmentaciji večjih delcev in posledično tvorbi močnejših povezav med novonastalimi čistimi površnami delcev. Obe osnovni zmesi sta zaradi boljše začetne prerazporeditve delcev izkazovali slabšo kompresibilnost in kompaktibilnost