Chacterization and optimization of binary and ternary solid dispersions and cyclodextrin-polymer systems as carriers with the aim of improving dissolution rate of poorly soluble drug

Formulacija farmaceutskih oblika za peroralnu primenu sa teško rastvorljivimlekovitim supstancama predstavlja sve veći problem usled niske biološke raspoloživostiovih supstanci koja je ograničena njihovom niskom brzinom rastvaranja. Formulacijačvrstih disperzija, u kojima je lekovita supstanca rastvorena ili dispergovana unutarpolimernog matriksa, predstavlja često korišćen pristup u cilju povećanja brzinerastvaranja teško rastvorljivih lekovitih supstanci. Iako se formulacijom čvrstihdisperzija često postiže značajno povećanje brzine rastvaranja teško rastvorljivihlekovitih supstanci, njihova primena je često ograničena faktorima kao što su: problemisa obezbeñenjem dugoročne stabilnosti lekovite supstance, visok odnos lekovitasupstanca:polimer i problemi sa formulacijom finalnog farmaceutskog oblika. Poredformulacije čvrstih disperzija, grañenje inkluzionih kompleksa lekovitih supstanci saciklodekstrinima takoñe predstavlja veoma efikasan pristup za povećanje brzinerastvaranja teško rastvorljivih lekovitih supstanci. Ipak, niska efikasnostkompleksiranja, uz veliku molekulsku masu ciklodekstrina često ograničava njihovuprimenu na formulaciju niskodoziranih lekovitih supstanci. Brojna istraživanja sesprovode kako bi se prevazišli nedostaci primene čvrstih disperzija i lekovita supstancaciklodekstrinkompleksa i neki od navedenih problema su razmatrani i u ovomistraživanju.U ovom istraživanju razmatrana je mogućnost primene čvrstih disperzija, binarnihlekovita supstanca-ciklodekstrin i ternarnih lekovita supstanca-ciklodekstrin-hidrofilnipolimer sistema kao nosača za povećanje brzine rastvaranja karbamazepina, kao teškorastvorljive i visokodozirane lekovite supstance koja pokazuje polimorfizam.U prvoj fazi istraživanja razmatrana je mogućnost primene binarnih čvrstihdisperzija karbamazepina sa poloksamerom 188 i poloksamerom 407 u cilju povećanjabrzine rastvaranja karbamazepina. Disperzije su izrañivane primenom metoda topljenjau karbamazepin:poloksamer masenim odnosima 1:1, 1:2 i 1:3. Rezultati fizičkohemijskekarakterizacije primenom diferencijalne skenirajuće kalorimetrije, polarizacionemikroskopije na zagrejanoj ploči i difrakcije X-zraka na prašku pokazali su da je svimuzorcima čvrstih disperzija karbamazepin prisutan u kristalnom obliku i to utermodinamički najstabilnijem polimorfnom obliku III (monoklinični oblik). PrimenomFT-IR spektroskopije pokazano je odsustvo karbamazepin-poloksamer interakcija, štozajedno sa težnjom molekula karbamazepina ka meñusobnoj agregaciji, uočenojprimenom simulacije molekularne dinamike predstavlja moguće objašnjenje za uočenukristalnu prirodu karbamazepina u uzorcima. Iz svih uzoraka čvrstih disperzijapostignuto je značajno povećanje brzine rastvaranja karbamazepina. Tako se tokomprvih 10 minuta ispitivanja rastvorilo više od 80% karbamazepina iz čvrstih disperzijaizrañenih sa poloksamerom 188 i 57-67% karbamazepina iz čvrstih disperzija izrañenihsa poloksamerom 407, dok se iz uzoraka čistog karbamazepina rastvorilo tek oko 15%ove lekovite supstance. Brže rastvaranje karbamazepina postignuto je iz čvrstihdisperzija izrañenih sa poloksamerom 188, u odnosu na čvrste disperzije sapoloksamerom 407, što se objašnjava većim udelom hidrofilnih etilen oksidnih lanacakod poloksamera 188. Sa povećanjem udela poloksamera došlo je do smanjenja brzinerastvaranja karbamazepina, što može predstavljati posledicu termoreverzibilnogelirajućih osobina poloksamera.U drugoj fazi istraživanja, prvi put je prikazana kombinovana primena tehnikaeksperimentalnog dizajna smeše i veštačkih neuronskih mreža u razvoju čvrstihdisperzija. Ternarne karbamazepin-Soluplus®-poloksamer 188 čvrste disperzijeizrañivane su metodom rastvaranja, uz variranje udela karbamazepina, Soluplus®-a ipoloksamera 188 u okviru unapred postavljenih granica. Iz izrañenih ternarnih čvrstihdisperzija postignuto je značajno povećanje brzine rastvaranja karbamazepina, pri čemuse u toku prvih 10 minuta ispitivanja, kod 11 od 22 izrañene formulacije, rastvorilo višeod 80% karbamazepina. Primenom D-optimalnog eksperimentalnog dizajna smeše iveštačkih neuronskih mreža tipa višeslojnog perceptrona dobijeni su modeli koji dobroopisuju zavisnost izmeñu udela svih komponenata u ternarnim karbamazepin-Soluplus®-poloksamer 188 čvrstim disperzijama i količine rastvorenog karbamazepina(%) nakon 10 (Q10) i 20 (Q20) minuta ispitivanja, što pokazuju dobijene vrednostikoeficijenta determinacije (R2) iznad 0,95. Dobijeni modeli pokazali su najveći uticajudela karbamazepina i poloksamera 188 na Q10 i Q20, pri čemu su najviše vrednosti ovihparametara zabeležene pri najvišim udelima poloksamera 188 (20%) i najnižim udelimakarbamazepina (20%). Proverom sposobnosti predviñanja dobijenih modela na test setupodataka pokazana je bolja sposobnost predviñanja modela veštačkih neuronskih mreža(R2=0,978) u odnosu na model dobijen primenom eksperimentalnog dizajna smeše(R2=0,741). Fizičkohemijskom karakterizacijom izrañenih formulacija pokazano je daje u svim uzorcima karbamazepin zastupljen u svom termodinamički najstabilnijempolimorfnom obliku III.U trećoj fazi istraživanja ispitivana je mogućnost primene karbamazepinhidroksipropil-β-ciklodekstrin binarnih i karbamazepin-hidroksipropil-β-ciklodekstrinhidrofilnipolimer ternarnih sistema u cilju povećanja brzine rastvaranja karbamazepina.Ispitivanjem fazne rastvorljivosti karbamazepina pokazano je da rastvorljivostkarbamazepina linearno raste (0,56-102,20 mmol/l) sa porastom koncentracijehidroksipropil-β-ciklodekstrina (0-40% m/v), dajući tzv. AL tip dijagrama faznerastvorljivosti, koji ukazuje na formiranje inkluzionih kompleksa karbamazepina sahidroksipropil-β-ciklodekstrinom u stehiometrijskom odnosu 1:1. Dodatkom hidrofilnihpolimera (Soluplus® i dva tipa hidroksipropilmetilceluloze različitog stepenasubstitucije i viskoziteta-Metolose® 90SH-100 i Metolose® 65SH-1500) rastvorimahidroksipropil-β-ciklodekstrina ostvaren je porast efikasnosti kompleksiranjahidroksipropil-β-ciklodekstrina za karbamazepin od 1,5 puta u odnosu na same rastvorehidroksipropil-β-ciklodekstrina. Simulacijom molekularne dinamike u sistemukarbamazepin-hidroksipropil-β-ciklodekstrin-hidroksipropilmetilceluloza pokazano jeda dolazi do interakcija izmeñu molekula karbamazepina koji disosuju iz kompleksa sahidroksipropil-β-ciklodekstrinom i hidroksipropilmetilceluloze. Uočene interakcijemogu sprečiti nastanak dimera karbamazepina i kristalizaciju slobodnih molekulakarbamazepina iz rastvora, što predstavlja moguće objašnjenje za uočen porastrastvorljivosti karbamazepina u rastvorima hidroksipropil-β-ciklodekstrina nakondodatka hidrofilnih polimera. Primenom tehnike sušenja raspršivanjem dobijeni subinarni karbamazepin-hidroksipropil-β-ciklodekstrin i ternarni karbamazepinhidroksipropil-β-ciklodekstrin-hidrofilni polimer sistemi iz kojih je postignuto značajnobrže rastvaranje karbamazepina, kako u odnosu na čist karbamazepin, tako i u odnosuna fizičke smeše ekvivalentnog sastava. Najveća brzina rastvaranja karbamazepinapostignuta je iz formulacija binarnih karbamazepin-hidroksipropil-β-ciklodekstrin iternarnih karbamazepin-hidroksipropil-β-ciklodekstrin-Soluplus® sistema, gde jecelokupna količina karbamazepina rastvorena već nakon 5 minuta ispitivanja. Kodformulacija izrañenih sa oba tipa hidroksipropilmetilceluloze (Metolose® 90SH-100 iMetolose® 65SH-1500) zabeleženo je nešto sporije i nepotpuno rastvaranjekarbamazepina i to naročito kod formulacije izrañene sa tipomhidroksipropilmetilceluloze većeg viskoziteta (Metolose® 65SH-1500), gde je zarastvaranje više od 90% karbamazepina bilo potrebno oko 60 minuta.Fizičkohemijskom karakterizacijom uzoraka pokazano je da je u svim formulacijamadobijenim sušenjem raspršivanjem karbamazepin prisutan u amorfnom obliku, što možeukazati na formiranje inkluzionih kompleksa sa hidroksipropil-β-ciklodekstrinom.Primenom tehnika simulacije molekularnog vezivanja karbamazepina i hidroksipropil-β-ciklodekstrina i simulacije molekularne dinamike pokazano je prisustvo hemijskihinterakcija izmeñu molekula karbamazepina i hidroksipropil-β-ciklodekstrina, što jepotvrñeno i primenom FT-IR spektroskopije. Uočene interakcije mogu značajnodoprineti stabilizaciji nastalih inkluzionih kompleksa.Na osnovu dobijenih rezultata, može se zaključiti da formulacija binarnih i ternarnihčvrstih disperzija, kao i lekovita supstanca-ciklodekstrin binarnih i lekovita supstancaciklodekstrin-hidrofilni polimer ternarnih sistema predstavlja uspešan formulacionipristup za povećanje brzine rastvaranja karbamazepina. Kako je karbamazepinvisokodozirana supstanca, prednost se može dati formulaciji binarnih i ternarnih čvrstihdisperzija, pošto sadrže visok udeo karbamazepina.Formulation of pharmaceutical dosage forms for peroral administration of poorlysoluble drugs represents growing problem due to their poor bioavailability, which islimited with their low dissolution rate. Formulation of solid dispersions where drug isdissolved or dispersed within the polymeric matrix is frequently used approach forimproving dissolution rate of poorly soluble drugs. Although significant improvementof drug dissolution rate is often achieved with solid dispersion formulation, theirapplication is often limited with factors, such as problems with ensuring of long termdrug stability, high drug:polymer ratios and problems with formulation of final dosageform. Besides solid dispersions formulation, formation of drug-cyclodextrin inclusioncomplexes is also very efficient approach for improving dissolution rate of poorlysoluble drugs. However, low complexation efficiency, together with high molecularweight of cyclodextrins often limits their application on the formulations with low dosedrugs. Numerous researches have been conducted to overcome aforementioneddrawbacks of solid dispersions and drug-cyclodextrins complexes and some of theseproblems were studied in this research.This study investigated possibility of using solid dispersions, binary drugcyclodextrinand ternary drug-cyclodextrin-hydrophilic polymer systems, as carriers forimproving dissolution rate of carbamazepine, as poorly soluble high dose drug thatexhibits polymorphism.First phase of research evaluated application of binary solid dispersions ofcarbamazepine with poloxamer 188 and poloxamer 407 for improving dissolution rateof carbamazepine. Solid dispersions were prepared by melting method incarbamazepine:poloxamer weight ratios of 1:1, 1:2 and 1:3. The results ofphysicochemical characterization obtained using differential scanning calorimetry, hotstagepolarized light microscopy and powder X-ray diffraction showed that in all soliddispersion samples, carbamazepine was present it the crystalline state, in its most stablepolymorphic form III (monoclinic form). FT-IR spectroscopy showed absence ofcarbamazepine-poloxamer interactions, which together with tendency of carbamazepinemolecules toward aggregation, observed using molecular dynamics simulation ispossible explanation for observed crystalline nature of carbamazepine in the samples.From all of the solid dispersion samples, significant increase of carbamazepinedissolution rate was observed. During the first 10 minutes of testing, more than 80% ofcarbamazepine was dissolved from poloxamer 188 solid dispersions and 57-67% frompoloxamer 407 solid dispersions, while only 15% of carbamazepine was dissolved fromthe samples of pure drug. Faster carbamazepine dissolution was achieved from soliddispersions prepared with poloxamer 188, compared to solid dispersions prepared withpoloxamer 407, which can be explained with higher proportion of hydrophilic ethyleneoxide chains in poloxamer 188. Increasing in the proportion of poloxamer led todecreasing of carbamazepine dissolution rate and this can be consequence ofthermoreversible gelation properties of poloxamers.The second phase of the research for the first time demonstrated combinedapplication of mixture experimental design and artificial neural networks in the soliddispersions development. Ternary carbamazepine-Soluplus®-poloxamer 188 soliddispersions have been prepared by solvent casting method, with variation in theproportions of carbamazepine, Soluplus® and poloxamer 188, within the predefinedconstraints. Significant increase of carbamazepine dissolution rate was achieved fromternary solid dispersions, wherein from 11 of 22 prepared formulations more than 80%of carbamazepine was dissolved during the first 10 minutes of testing. D-optimalmixture experimental design and multi layer perceptron artificial neural networks gavemodels that well describe dependence between proportions of all components in theternary carbamazepine-Soluplus®-poloxamer 188 solid dispersions and amount ofdissolved carbamazepine (%) after 10 (Q10) and 20 (Q20) minutes of the testing, asindicated by the coefficient of determination (R2) higher than 0.95. Obtained modelsshowed the largest influence of the proportions of carbamazepine and poloxamer 188 onboth Q10 and Q20, wherein the highest values of these parameters were observed withthe highest proportions of poloxamer 188 (20%) and the lowest proportions ofcarbamazepine (20%). Testing of the predictability of the obtained models on test dataset showed better predictability of artificial neural network model (R2=0.978),compared to mixture experimental design model (R2=0.741). Physicochemicalcharacterization of prepared formulations showed presence of the most stable crystallinepolymorphic form III of carbamazepine in all samples.Third phase of the research studied possibility of using binary carbamazepinehydroxypropyl-β-cyclodextrin and ternary carbamazepine-hydroxypropyl-β-cyclodextrin-hydrophilic polymer systems with the aim to increase carbamazepinedissolution rate. Phase solubility study showed linear increase of carbamazepinesolubility (0.56-102.20 mmol/l) with increase of hydroxypropyl-β-cyclodextrinconcentration (0-40% m/v), giving AL-type phase solubility plot that indicates formationof carbamazepine-hydroxypropyl-β-cyclodextrin inclusion complex in 1:1stoichiometric ratio. Addition of hydrophilic polymers (Soluplus® and two types ofhydroxypropyl methylcellulose of different degree of substitution and viscosity-Metolose® 90SH-100 and Metolose® 65SH-1500) to hydroxypropyl-β-cyclodextrinsolutions led to 1.5 times increase of complexation efficiency of hydroxypropyl-β-cyclodextrin for carbamazepine, compared to pure hydroxypropyl-β-cyclodextrinsolutions. Molecular dynamics simulation in carbamazepine-hydroxypropyl-β-cyclodextrin-hydroxypropyl methylcellulose system showed interactions betweenhydroxypropyl methylcellulose and carbamazepine molecules that dissociate fromcomplexes with hydroxypropyl-β-cyclodextrin. Observed interactions can preventformation of carbamazepine dimers and crystallization of free carbamazepine moleculesfrom the solution and this can be possible explanation for observed increase ofcarbamazepine solubility in the hydroxypropyl-β-cyclodextrin solutions upon additionof hydrophilic polymers. By using of spray drying technique, both binarycarbamazepine-hydroxypropyl-β-cyclodextrin and ternary carbamazepinehydroxypropyl-β-cyclodextrin-hydrophilic polymer systems were prepared, whichresulted in significantly higher carbamazepine dissolution rate compared to both purecarbamazepine, as well as to physical mixtures of equivalent composition. The highestcarbamazepine dissolution rate was achieved from formulations of binarycarbamazepine-hydroxypropyl-β-cyclodextrin and ternary carbamazepinehydroxypropyl-β-cyclodextrin-Soluplus® systems, where the entire amount ofcarbamazepine was dissolved after 5 minutes of testing. Formulations prepared withboth types of hydroxypropyl methylcellulose (Metolose® 90SH-100 and Metolose®65SH-1500) exhibit somewhat slower and incomplete carbamazepine dissolution,particularly in the case of formulation prepared with hydroxypropyl methylcellulosetype of higher viscosity (Metolose® 65SH-1500), where 60 minutes was necessary fordissolution of more than 90% of carbamazepine. Physicochemical characterizationshowed presence of amorphous carbamazepine in all formulations prepared by spraydrying, which can indicate on the formation of inclusion complexes withhydroxypropyl-β-cyclodextrin. Molecular docking simulation between carbamazepineand hydroxypropyl-β-cyclodextrin and molecular dynamics simulations showedpresence of chemical interactions between carbamazepine and hydroxypropyl-β-cyclodextrin molecules, which was confirmed by using of FT-IR spectroscopy.Observed interactions can significantly contribute to stabilization of the resultinginclusion complexes.Based on the obtained results, it can be concluded that formulation of binary andternary solid dispersions as well as binary drug-cyclodextrin and ternary drugcyclodextrin-hydrophilic polymer systems represent successful formulation approachfor improving solubility of carbamazepine. Since carbamazepine is administered in highdoses, preference can be given to the formulation of binary and ternary solid dispersionswhich contain higher carbamazepine content

Diatoms - nature materials with great potential for bioapplications

Diatoms are widespread unicellular photosynthetic algae that produce unique highly ordered siliceous cell wall, called frustule. Micro- to nanoporous structure with high surface area that can be easily modified, high mechanical resistance, unique optical features (light focusing and luminescence) and biocompatibility make diatom frustule as a suitable raw material for the development of devices such as bio- and gas sensors, microfluidic particle sorting devices, supercapacitors, batteries, solar cells, electroluminescent devices and drug delivery systems. Their wide availability in the form of fossil remains (diatomite or diatomaceous earth) as well as easy cultivation in the artificial conditions further supports use of diatoms in many different fields of application. This review focused on the recent achievements in the diatom bioapplications such as drug delivery, biomolecules immobilization, bio- and gas sensing, since great progress was made in this field over the last several years

Insight into the formation of glimepiride nanocrystals by wet media milling

Nanocrystal formation for the dissolution enhancement of glimepiride was attempted by wet media milling. Di erent stabilizers were tested and the obtained nanosuspensions were solidified by spray drying in presence of mannitol, and characterized regarding their redispersibility by dynamic light scattering, physicochemical properties by di erential scanning calorimetry (DSC), FT-IR spectroscopy, powder X-ray di raction (PXRD), and scanning electron microcopy (SEM), as well as dissolution rate. Lattice energy frameworks combined with topology analysis were used in order to gain insight into the mechanisms of particle fracture. It was found that nanosuspensions with narrow size distribution can be obtained in presence of poloxamer 188, HPC-SL and Pharmacoat® 603 stabilizers, with poloxamer giving poor redispersibility due to melting and sticking of nanocrystals during spray drying. DSC and FT-IR studies showed that glimepiride does not undergo polymorphic transformations during processing, and that the milling process induces changes in the hydrogen bonding patterns of glimepiride crystals. Lattice energy framework and topology analysis revealed the existence of a possible slip plane on the (101) surface, which was experimentally verified by PXRD analysis. Dissolution testing proved the superior performance of nanocrystals, and emphasized the important influence of the stabilizer on the dissolution rate of the nanocrystals

Tailoring Atomoxetine Release Rate from DLP 3D-Printed Tablets Using Artificial Neural Networks: Influence of Tablet Thickness and Drug Loading

Various three-dimensional printing (3DP) technologies have been investigated so far in relation to their potential to produce customizable medicines and medical devices. The aim of this study was to examine the possibility of tailoring drug release rates from immediate to prolonged release by varying the tablet thickness and the drug loading, as well as to develop artificial neural network (ANN) predictive models for atomoxetine (ATH) release rate from DLP 3D-printed tablets. Photoreactive mixtures were comprised of poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) 400 in a constant ratio of 3:1, water, photoinitiator and ATH as a model drug whose content was varied from 5% to 20% (w/w). Designed 3D models of cylindrical shape tablets were of constant diameter, but different thickness. A series of tablets with doses ranging from 2.06 mg to 37.48 mg, exhibiting immediate- and modified-release profiles were successfully fabricated, confirming the potential of this technology in manufacturing dosage forms on demand, with the possibility to adjust the dose and release behavior by varying drug loading and dimensions of tablets. DSC (differential scanning calorimetry), XRPD (X-ray powder diffraction) and microscopic analysis showed that ATH remained in a crystalline form in tablets, while FTIR spectroscopy confirmed that no interactions occurred between ATH and polymers

In vitro and in vivo investigation of taste-masking effectiveness of Eudragit E PO as drug particle coating agent in orally disintegrating tablets

Context: Considering that bitter taste of drugs incorporated in orally disintegrating tablets (ODTs) can be the main reason for avoiding drug therapy, it is of the utmost importance to achieve successful taste-masking. The evaluation of taste-masking effectiveness is still a major challenge. Objective: The objective of this study was to mask bitter taste of the selected model drugs by drug particle coating with Eudragit (R) E PO, as well as to evaluate taste-masking effectiveness of prepared ODTs using compendial dissolution testing, dissolution in the small-volume shake-flask assembly and trained human taste panel. Materials and methods: Model drugs were coated in fluidized bed. Disintequik (TM) ODT was used as a novel co-processed excipient for ODT preparation. Selected formulations were investigated in vitro and in vivo using techniques for taste-masking assessment. Results and discussion: Significantly slower drug dissolution was observed from tablets with coated drug particles during the first 3 min of investigation. Results of in vivo taste-masking assessment demonstrated significant improvement in drug bitterness suppression in formulations with coated drug. Strong correlation between the results of drug dissolution in the small-volume shake-flask assembly and in vivo evaluation data was established (R >= 0.970). Conclusion: Drug particle coating with Eudragit (R) E PO can be a suitable approach for bitter taste-masking. Strong correlation between in vivo and in vitro results implicate that small-volume dissolution method may be used as surrogate for human panel taste-masking assessment, in the case of physical taste-masking approach application.This is peer-reviewed version of the following article: Drašković, M.; Medarević, D.; Aleksić, I.; Parojčić, J. In Vitro and in Vivo Investigation of Taste-Masking Effectiveness of Eudragit E PO as Drug Particle Coating Agent in Orally Disintegrating Tablets. Drug Dev. Ind. Pharm. 2017, 43 (5), 723–731. [https://doi.org/10.1080/03639045.2016.1220572

Powder bed fusion–laser beam (PBF-LB) three-dimensional (3D) printing: Influence of laser hatching distance on the properties of zolpidem tartrate tablets

Laser sintering, known as powder bed fusion–laser beam (PBF-LB), offers promising potential for the fabrication of patient-specific drugs. The aim of this study was to provide an insight into the PBF-LB process with regard to the process parameters, in particular the laser hatching distance, and its influence on the properties of zolpidem tartrate (ZT) tablets. PHARMACOAT® 603 was used as the polymer, while Candurin® Gold Sheen and AEROSIL® 200 were added to facilitate 3D printing. The particle size distribution of the powder blend showed that the layer height should be set to 100 µm, while the laser hatching distance was varied in five different steps (50, 100, 150, 200 and 250 µm), keeping the temperature and laser scanning speed constant. Increasing the laser hatching distance and decreasing the laser energy input led to a decrease in the colour intensity, mass, density and hardness of the ZT tablets, while the disintegration and dissolution rate were faster due to the more fragile bonds between the particles. The laser hatching distance also influenced the ZT dosage, indicating the importance of this process parameter in the production of presonalized drugs. The absence of drug-polymer interactions and the amorphization of the ZT were confirmed

Ispitivanje uticaja faktora formulacije i procesa na oslobađanje tramadol hidrohlorida i mehaničke karakteristike matriks tableta sa produženim oslobađanjem

This study investigates the use of high molecular weight polyethylene oxide (PEO WSR coagulant) for the preparation of sustained release matrix tablets containing high dose, highly water soluble drug, tramadol HCl. Proportion of PEO polymer, type of insoluble filler, proportion of tramadol HCl, amount of drug in tablet, tablet diameter and compression pressure were recognized as critical formulation and process parameters and their influence on drug release and tablet mechanical properties was evaluated. Percentages of tramadol HCl released after 30 and 240 min were selected for evaluation of drug release, while tensile strength was used as indicator of tablet mechanical properties. Only proportion of tramadol HCl exhibits statistically significant effect on percentages of tramadol HCl released after 30 and 240 min, with higher, wherein increasing of the tramadol HCl proportion increased its release rate among the evaluated variables in selected ranges. All of the investigated factors exhibit statistically significant effect on tablets tensile strength, with the largest influence of filler type. Tablets prepared with highly compressible filler (microcrystalline cellulose) exhibit higher tensile strength and therefore better mechanical properties to those prepared with partially pregelatinized starch (starch 1500).U radu je ispitivan uticaj formulacijskih i procesnih promenljivih na brzinu oslobađanja i mehaničke karakteristike matriks tableta izrađenih sa polietilen oksidom velike molekulske mase (PEO WSR koagulant), kao matriks formirajućim materijalom i visoko rastvoljivom lekovitom supstancom prisutnoj u velikoj dozi, tramadol hidrohloridom. Kao formulacijske promenljive varirane su: udeo polietilen oksidnog polimera (25 ili 35%), vrsta nerastvornog sredstva za dopunjavanje (mikrokristalna celuloza i parcijalno pregelirani skrob), udeo tramadol hidrohlorida (27,8 i 55,6%), količina leka u tableti (100 ili 200 mg). Pritisak kompresije je variran kao procesna promenljiva. Procenat tramadol hidrohlorida rastvoren nakon 30 i 240 min ispitivanja je izabran kao zavisno promenljiva za ispitivanje oslobađanja lekovite supstance, dok je zatezna čvrstoća izabrana kao zavisno promenljiva koja je indikator mehaničkih karakteristika tableta. Izvedena su dva seta eksperimenata, koji odgovaraju 25-2, odnosno 23 eksperimentalnom dizajnu. Tablete su izrađene na simulatoru kompakcije Prester. Simuliran je rad rotacione tablet prese Korch PH336, sa brzinom rotacije 30 rpm, što odgovara kapacitetu od 65000 tableta na sat. Ispitivanje uticaja faktora formulacije i procesa na oslobađanje tramadol hidrohlorida pokazalo je da se iz svih formulacija tramadol hidrohlorid oslobađa usporeno, linearnom kinetikom. Najveći uticaj na procenat oslobođenog leka imao je udeo leka u tableti. Sa povećanjem udela leka u tableti, povećavao se i procenat oslobođenog leka u navedenim vremenskih intervalima. Ostali isptivani faktori nisu imali značajan uticaj na brzinu oslobađanja. Ispitivanje mehaničkih karakteristika tableta pokazalo je da na zateznu čvrstoću izrađenih tableta najveći uticaj ima vrsta sredstva za dopunjavanje. Najveće vrednosti zatezne čvrstoće su dobijene u slučaju kada je mikrokristalna celuloza korišćena kao sredstvo za dopunjavanje, kao i kada je procenat polimera u tableti bio na višem nivou. Analiza dobijenih rezultata omogućava pravilan izbor vrste i koncentracije pomoćnih materija u formulaciji matriks tableta sa produženim oslobađanjem izrađenih sa polietilen oksidnim polimerom i visoko rastvorljivom lekovitom supstancom prisutnoj u velikoj dozi

Supercritical CO2 utilization in preparation of poorly soluble drugs solid dispersions

Formulation of solid dispersions is one of the most feasible strategies for overcoming the poor drugs’ solubility – one of the major issues affecting drug bioavailability and therapeutic outcomes. Since traditional methods used for preparation of solid dispersions often require usage of organic solvents, it is of great importance to seek for more environment-friendly methods. It has been demonstrated that supercritical (sc) CO2 may be effectively utilized for dispersion of drugs into the suitable carrier (polymer), thus obtaining solid dispersions with the improved drug dissolution rate. The aim of the presented study was to investigate the potential of scCO2 for preparation of poorly soluble antihypertensive drugs (carvedilol and valsartan) solid dispersions in the conventional pharmaceutical polymers (polyvinilypyrolidone-PVP and hypromellose-HPMC). Prepared solid dispersions were characterized by scanning electron microscopy, differential scanning calorimetry and Fourier-transform infrared spectroscopy; their porosity and density were determined and drug dissolution rate was assessed and compared to the results obtained from solid dispersions prepared by the traditional solvent casting method. Selected samples were tested for their tableting properties as well. It has been demonstrated that scCO2 may be successfully applied for preparation of carvedilol or valsartan solid dispersions with the improved drug dissolution rate. Further characterization revealed the nature of interactions between the drugs and selected polymers. Due to the low density (and high porosity), some of the prepared solid dispersions may be used for further development of the floating dosage forms. It has also been demonstrated that some of the prepared dispersions have excellent compressibility and compactibility, which is of great importance for further development of solid dosage forms. The obtained results provide framework for further development of environment-friendly methods in pharmaceutical development and production

Poređenje oslobađanja tramadol-hidrohlorida i mehaničkih karakteristika matriks tableta izrađenih sa odabranim hidrofilnim polimerima

This study investigates the use of high molecular weight hydrophilic polymers, hypromellose and hydroxypropylcellulose, for the preparation of sustained release matrix tablets containing a high-dose highly soluble drug, tramadol HCl. The proportion of polymer, type of insoluble filler, proportion of tramadol HCl, amount of drug in the tablet and compression pressure were recognized as critical formulation and process parameters and their influence on drug release and tablet mechanical properties was evaluated. Tensile strength was used as an indicator of the mechanical properties of the tablets. Experiments were performed with utilization of a compaction simulator, a device that simulates compaction profiles of large scale rotary tablet presses. In formulations with both polymers, the proportion of tramadol HCl was the most critical formulation parameter, wherein increasing the proportion of tramadol HCl increased its release rate in the early stages of drug release. Regarding the tablet mechanical characteristics, the filler type had the most pronounced effect in formulations with both polymers. Higher tensile strengths were obtained with Avicel PH 102 as the filler in formulations with both HPMC and HPC.U ovom radu ispitivana je mogućnost primene hipromeloze i hidroksipropilceluloze, kao hidrofilnih polimera velike molekulske mase, za izradu matriks tableta sa produženim oslobađanjem, sa visoko rastvorljivom, visoko doziranom lekovitom supstancom tramadol-hidrohloridom. Udeo hidrofilnog polimera, vrsta nerastvorljivog sredstva za dopunjavanje, udeo tramadol-hidrohlorida, količina lekovite supstance u pojedinačnoj tableti i pritisak kompresije su prepoznati kao kritični parametri formulacije i procesa i u radu je ispitivan njihov uticaj na oslobađanje lekovite supstance i mehaničke karakteristike izrađenih tableta. Zatezna čvrstina tableta je korišćena kao indikator mehaničkih karakteristika tableta. Svi eksperimenti su vršeni korišćenjem simulatora kompakcije, koji omogućava simuliranje profila kompakcije rotacionih tablet mašina velikog kapaciteta. Kod formulacija izrađenih sa obe vrste polimera, udeo tramadol-hidrohlorida se pokazao kao najkritičniji faktor formulacije, pri čemu je povećanje udela tramadol-hidrohlorida dovelo do povećanja brzine oslobađanja ove lekovite supstance u početnim fazama oslobađanja lekovite supstance. Vrsta sredstva za dopunjavanje je pokazala najveći uticaj na mehaničke karakteristike izrađenih tableta, kod formulacija izrađenih sa oba tipa hidrofilnih polimera. Više vrednosti zatezne čvrstine tableta su postignute kod formulacija izrađenih korišćenjem Avicel PH 102 kao sredstva za dopunjavanje, bez obzira da li je u sastav tableta kao matriks polimer ulazila hipromeloza ili hidroksipropilceluloza

Formulation and characterization of desloratadine mini-tablets obtained by photopolimerization 3D printing technique

3D štampa lekova, kao aditivna tehnologija, predstavlja jednostavnu i ekonomski prihvatljivu alternativu konvencionalnim metodama, pružajući mogućnost dobijanja inovativnih farmaceutskih oblika i prilagođavanje terapije individualnim potrebama pacijenata (1). Cilj istraživanja bio je da se formulišu i izrade mini tablete desloratadinа (DSL) primenom 3D tehnike digitalne obrade svetlosti (engl. Digital light processing, DLP) mehanizmom nanošenja materijala “sloj po sloj”. Mini tablete DSL (10%, m/m) odabrane su kao farmaceutski oblik leka koji je pogodan za primenu u pedijatrijskoj populaciji, pre svega sa aspekta fleksibilnosti doziranja. Pripremljena je formulacija sa 1% fotoinicijatora i 10% vode, dok su polietilenglikol-diakrilat i polietilenglikol 400 bili prisutni u masenom odnosu 1:1. Kreirani 3D modeli (4,00 × 3,00 mm) uspešno su odštampani primenom WanhaoD8 štampača. Dobijene su žuto-narandžaste mini tablete uniformnog oblika, debljine i mase (4,16 ± 0,06 × 2,24 ± 0,04 mm; 42,61 ± 1,15 mg). Nepotpuna ekstrakcija DSL iz unakrsno umreženog polimernog matriksa rezultovala je relativno niskim sadržajem lekovite supstance u mini tabletama u odnosu na teorijski sadržaj (72,14 ± 1,04%) (2). Prilikom ispitivanja brzine rastvaranja, nakon 45 min oslobođeno je 50,29 ± 0,14% DSL u 0,1M hlorovodoničnoj kiselini, kao medijumu, uz postizanje platoa nakon 4 sata (81,19 ± 0,63%). Rezultati DSC analize pokazali su da je došlo do amorfizacije lekovite supstance, dok je posmatranjem poprečnih preseka odštampanih mini tableta pod polarizacionim svetlosnim mikroskopom uočeno prisustvo slojevite strukture. DLP tehnika 3D štampe lekova ima potencijal da obezbedi brzu izradu mini tableta odgovarajućih fizičko-hemijskih karakteristika, uz mogućnost postizanja modifikovanog oslobađanja lekovite supstance.3D printing as an additive technology represents a simple and economically acceptable alternative to conventional methods and offers the possibility of obtaining innovative dosage forms and individualizing therapy according to the specific needs of patients. (1). The aim of the research was to formulate and manufacture desloratadine mini-tablets (DSL) using digital light processing (DLP) 3D technique based on a successive layering mechanism. Mini-tablets of DSL (10%,w/w) were selected as a dosage form suitable for the pediatric population, particularly because of its flexible dosing. The formulation was prepared with 1% photoinitiator and 10% water, while poly(ethylene glycol) diacrylate and poly(ethylene glycol) 400 were present in a mass ratio of 1:1. The created 3D models (4.00×3.00 mm) were successfully printed using WanhaoD8 printer. Yellow-orange mini- tablets with uniform shape, thickness and mass (4.16±0.06×2.24±0.04 mm; 42.61±1.15 mg) were produced. Incomplete extraction of DSL from the cross-linked polymer matrix resulted in a relatively low content of the drug in the mini-tablets compared to the theoretical content (72.14±1.04%) (2). The dissolution test showed that 50.29±0.14% of DSL was released after 45 minutes in 0.1M hydrochloric acid medium and reached a plateau after 4 hours (81.19±0.63%). The results of DSC analysis showed amorphisation of the drug, while observation of the cross-sections of printed mini- tablets under a polarizing microscope indicated the presence of a layered structure. The DLP technique has the potential to ensure the rapid production of mini-tablets with suitable physicochemical properties and to enable modified release of the drug.Treći naučni simpozijum Saveza farmaceutskih udruženja Srbije sa međunarodnim učešćem „Lekovi za specifične populacije pacijenata: inovacijama ka unapređenju zdravstvenih ishoda“, Niš, Srbija, 26. oktobar 2023