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Nutrition and dietary supplements have a significant role in the prevention and treatment of cardiovascular disease. Olive and vine leaves, thanks to their constituents, represent powerful natural antioxidants exhibiting cardioprotective activity. High concentrations of active ingredients can be provided by means of extraction. Dry herbal extracts are highly sensitive to moisture and elevated temperature and from the pharmaceutical and technological point of view these are raw materials with inadequate technological properties. The aim of this study was to investigate and to compare the influence of different excipients in capsule formulation of these two dry extracts i.e. the selection of excipients that will ensure appropriate critical process parameters in the manufacturing procedure. The monitored quality characteristics include flowability, bulk density and tapped density that are critical for technological feasibility of the capsule-filling operation. The effects of excipients on the above parameters have been experimentally studied and the appropriate capsule formulations have been developed based on the obtained results, which will ensure homogeneity and stability of the preparation.

Vlažna granulacija je složen proizvodni proces izrade tableta. Ovaj proces je podložan uticaju mnogobrojnih varijabli, što predstavlja izazov prilikom transfera proizvodne tehnologije. Predmet istraživanja doktorske disertacije je olakšanje pocesa transfera tehnologije vlažne granulacije korišćenjem pristupa principa dizajna kvaliteta (engl. Quality by design – QbD) i različitih algoritama mašinskog učenja.Prvi deo ovog rada istražuje značaj i obim uticaja formulacionih i procesnih promenljivih na kritične atribute kvaliteta (engl. Critical quality attributes – CQA) tableta. Istraživan je uticaj nerastvornog punioca trikalcijum-fosfata (TKF) na vreme raspadanja i čvrstinu tableta u procesu vlažne granulacije. Ovaj ekscipijens nije prethodno izučavan u ovom kontekstu zbog toga što se u farmaceutskom razvoju najčešće zamenjuje dikalcijum-fosfatom. Uticaj koncentracije trikalcijum-fosfata i superdezintegratora natrijum-skrobglikolata (NSG) i uticaj procesnih parametara (količina vode u rastvoru za granulaciju, veličina otvora sita i sadržaj vlage) su procenjeni istovremeno u cilju razvoja matematičkih modela za predviđanje kritičnih atributa kvaliteta tableta (vreme raspadanja i čvrstina) i uspešnog vođenja procesa transfera tehnologije vlažne granulacije. Povećana koncentracija natrijum-skrobglikolata je skratila vreme raspadanja ali je imala negativan uticaj na čvrstinu tableta. Procesni parametar sa najviše uticaja na vreme raspadanja je bio sadržaj vlage dok je veličina otvora na situ (koje je korišćeno prilikom mlevenja suvog granulata) bio najznačajniji procesni parametar za čvrstinu tableta. Pri upotrebi sita sa manjom veličinom otvora u procesu mlevenja dobijeni su optimalni rezultati za analizirane atribute kvaliteta tableta kad je količina vode u rastvoru za granulaciju bila na višem nivou. Kada je za mlevenje granula korišćeno sito sa većom veličinom otvora, najbolji rezultati za atribute kvaliteta tableta su dobijeni kad je količina vode u rastvoru za granu, Wet granulation is a complex manufacturing process. It is influenced by the multiple variables which presents challenges to the scale-up process. The objective of this PhD dissertation research is to use a quality by design (QbD) approach i multiple machine learning algorithms in facilitating wet granulation process scale-up.The first part of this reseach investigates the significance i extent of influence of both formulation i process variables on the critical quality attributes (CQAs) of tablets. The influence of insoluble diluent - tribasic calcium phosphate on disintegration time i tablet hardness, in the wet granulation process, was examined. This excipient was not previously studied in this context as it is frequently replaced with dicalcium phosphate in the pharmaceutical development practice. The influence of tricalcium phosphate i the superdisintegrant sodium starch glycolate, as well as the influence of process parameters (water concentration in granulation solution, screen hole size i moisture content) were used together to develop mathematical models that could be used in prediction of tablet CQAs (disintegration time i hardness) i facilitate wet granulation scale up process. Higher concentrations of sodium starch glycolate shortened disintegration time but negatively influenced tablet hardness. The most significant factor influencing disintegration time was moisture content while a screen hole size (used for dry granulate milling) was the most significant factor influencing tablet hardness. The use of a smaller screen hole size in milling process produced the optimal results for tablet quality attributes when water amount in granulation solution was high. The best results for tablet quality attributes are achieved when a larger hole screen size, used in milling process, was applied in conjuction with the low water amount, used in granulation process. Developed mathematical models describe the influence of analysed parameters on disintegration time i tab

Vlažna granulacija je složen proizvodni proces izrade tableta. Ovaj proces je podložan uticaju mnogobrojnih varijabli, što predstavlja izazov prilikom transfera proizvodne tehnologije. Predmet istraživanja doktorske disertacije je olakšanje pocesa transfera tehnologije vlažne granulacije korišćenjem pristupa principa dizajna kvaliteta (engl. Quality by design – QbD) i različitih algoritama mašinskog učenja. Prvi deo ovog rada istražuje značaj i obim uticaja formulacionih i procesnih promenljivih na kritične atribute kvaliteta (engl. Critical quality attributes – CQA) tableta. Istraživan je uticaj nerastvornog punioca trikalcijum-fosfata (TKF) na vreme raspadanja i čvrstinu tableta u procesu vlažne granulacije. Ovaj ekscipijens nije prethodno izučavan u ovom kontekstu zbog toga što se u farmaceutskom razvoju najčešće zamenjuje dikalcijum-fosfatom. Uticaj koncentracije trikalcijum-fosfata i superdezintegratora natrijum-skrobglikolata (NSG) i uticaj procesnih parametara (količina vode u rastvoru za granulaciju, veličina otvora sita i sadržaj vlage) su procenjeni istovremeno u cilju razvoja matematičkih modela za predviđanje kritičnih atributa kvaliteta tableta (vreme raspadanja i čvrstina) i uspešnog vođenja procesa transfera tehnologije vlažne granulacije. Povećana koncentracija natrijum-skrobglikolata je skratila vreme raspadanja ali je imala negativan uticaj na čvrstinu tableta. Procesni parametar sa najviše uticaja na vreme raspadanja je bio sadržaj vlage dok je veličina otvora na situ (koje je korišćeno prilikom mlevenja suvog granulata) bio najznačajniji procesni parametar za čvrstinu tableta. Pri upotrebi sita sa manjom veličinom otvora u procesu mlevenja dobijeni su optimalni rezultati za analizirane atribute kvaliteta tableta kad je količina vode u rastvoru za granulaciju bila na višem nivou. Kada je za mlevenje granula korišćeno sito sa većom veličinom otvora, najbolji rezultati za atribute kvaliteta tableta su dobijeni kad je količina vode u rastvoru za gran, Wet granulation is a complex manufacturing process. It is influenced by the multiple variables which presents challenges to the scale-up process. The objective of this PhD dissertation research is to use a quality by design (QbD) approach i multiple machine learning algorithms in facilitating wet granulation process scale-up. The first part of this reseach investigates the significance i extent of influence of both formulation i process variables on the critical quality attributes (CQAs) of tablets. The influence of insoluble diluent - tribasic calcium phosphate on disintegration time i tablet hardness, in the wet granulation process, was examined. This excipient was not previously studied in this context as it is frequently replaced with dicalcium phosphate in the pharmaceutical development practice. The influence of tricalcium phosphate i the superdisintegrant sodium starch glycolate, as well as the influence of process parameters (water concentration in granulation solution, screen hole size i moisture content) were used together to develop mathematical models that could be used in prediction of tablet CQAs (disintegration time i hardness) i facilitate wet granulation scale up process. Higher concentrations of sodium starch glycolate shortened disintegration time but negatively influenced tablet hardness. The most significant factor influencing disintegration time was moisture content while a screen hole size (used for dry granulate milling) was the most significant factor influencing tablet hardness. The use of a smaller screen hole size in milling process produced the optimal results for tablet quality attributes when water amount in granulation solution was high. The best results for tablet quality attributes are achieved when a larger hole screen size, used in milling process, was applied in conjuction with the low water amount, used in granulation process. Developed mathematical models describe the influence of analysed parameters on disintegration time i ta

Three-dimensional (3D) printing enables the production of different objects adjusted for the specific application, which has particular importance of providing personalized therapy, whereby the challenge is to apply pharmaceutical materials into 3D printing technology. In this study, effect of poly(ethylene glycol) 400 (PEG 400), sodium chloride (NaCl), and mannitol, as hydrophilic excipients, was investigated in order to overcome very slow and incomplete drug release from tablets (printlets) fabricated by photopolymerization using digital light processing (DLP) technology. Paracetamol (acetaminophen) was used as a model drug, while polyethylene glycol diacrylate (PEGDA) was used as a photopolymer and diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide as a photoinitiator in photoreactive mixtures. Most of printlet formulations exhibit sustained release over 8 h, wherein drug release kinetics is the best described with Korsmeyer-Peppas kinetics. Variation in the content of photopolymer and excipients had an influence on the dissolution rate, mechanical characteristics, and internal structure of the investigated samples. The addition of hydrophilic polymers increased drug release rate, while PEGDA had the greatest influence on the tensile strength of printlets. The results indicate the possibility of implementation of traditional excipients into different formulations for photopolymerization based 3D printing for the production of small batches of tablets with tailored drug release.

U radu su formulisane i ispitane i formulisane različiti čvrsti samodispergujući sistemi kao potencijalni nosači za teško rastvorljivu model lekovitu supstancu karbamazepin (CBZ). Ispitivani su: čvrsti samomikroemulgujući sistem (eng. Solid Self-microemulsifying drug delivery system, skr. SSMEDDS), čvrsta samomulgujuća fosfolipidna suspenzija (eng. Solid Self-emulsifying phospholipid suspension, skr. SSEPS) kao i samoemulgujuće pelete. Samomikroemulgujući sistem (eng. Self-microemulsifying drug delivery system - SMEDDS) je fomulisan korišćenjem surfaktanta (Polisorbat 80 (S)), kosurfaktanta (PEG – 40 hidrogenizovano ricinusovo ulje (C)) i uljane faze (trigliceridi srednje dužine lanca (O)). Prilikom izrade SSMEDDS sistema korišćena su četiri različita adsorbensa velike specifične aktivne površine, pri čemu su dva bila tipa magnezijum-aluminometasilikata (Neusilin® UFL2 i Neusilin® FL2) i dva tipa silicijum-dioksida (Sylysia® 320 i Sylysia® 350). Ispitana je mikroemulziona oblast sistema pri odnosu surfaktanta i kosurfaktanta (Km) 1:1 i SMEDDS formulacija sa surfaktant-kosurfaktant/ulje odnosom (eng. surfactant-cosurfactant/oil ratio - SC/O) 8/2 je izabrana za dalja istraživanja. Kapacitet solubilizacije odabrane SMEDDS formulacije za CBZ iznosio je 33771 ± 41 μg/ml. Reološka merenja SMEDDS formulacije sa i bez CBZ, pri sadržaju vode od 10 do 60 % (m/m), su pokazala da nakon razblaženja sa vodom CBZ ima znatan uticaj na reološko ponašanje ispitivanih sistema. Fotonska korelaciona spektroskopija je pokazala sposobnost formulacije da, nakon razblaženja sa vodom, formira kapi čiji prečnik odgovara mikroemulzijama. SSMEDDS formulacije su znatno poboljšale brzinu rastvaranja CBZ, pri čemu je pokazano da vrsta adsorbensa znatno utiče na brzinu rastvaranja. Kod formulacija sa adsorbensom tipa magnezijum-aluminometasilikata brzina rastvaranja CBZ opada sa porastom specifične aktivne površine, usled zadržavanja dela tečne SMEDDS unutar pora sistema i njegovom postepenom izlag, The purpose of this study was to investigate different solid self-dispersing formulations as potential drug delivery system for poorly soluble carbamazepine (CBZ). Solid selfmicroemulsifying drug delivery system (SSMEDDS), solid self-emulsifying phospholipid suspension (SSEPS) and self-emulsifying pellet formulations were investigated. Selfmicroemulsifying drug delivery system (SMEDDS) was formulated using the surfactant polyoxyethylene 20 sorbitan monooleate (S), the cosurfactant PEG-40 hydrogenated castor oil (C) and the oil caprylic/capric triglycerides (O). Four different adsorbents with high specific surface area were used: Neusilin® UFL2, Neusilin® FL2 (magnesium aluminometasilicate), Sylysia® 320 and Sylysia® 350 (porous silica). Microemulsion area at the surfactant to cosurfactant ratio (Km) 1:1 was evaluated and for further investigation SMEDDS with SC/O ratio 8:2 was selected. Solubilization capacity of selected SMEDDS for CBZ was 33771 ± 41 μg/ml. Rheological measurements of unloaded and CBZ-loaded SMEDDS system at water content varied from 10 to 60 % (w/w) were conducted. It has been found that CBZ has great influence on rheological behaviour of investigated system upon water dilution. Photon correlation spectroscopy has shown ability of CBZ-loaded SMEDDS system to produce microemulsion droplet size. SSMEDDS improved release rate of CBZ, but type of adsorbent significantly affects release rate of CBZ. For SSMEDDS with different magnesium aluminometasilicate adsorbents, release rate of CBZ decreased with increasing specific surface area due to entrapment of liquid SMEDDS inside the pores and its gradual exposure to dissolution medium. With porous silica adsorbents no difference in release rate was found in comparison to physical mixtures. In physical mixtures presence of amorphous CBZ led to high dissolution rate. Self – emulsifying phospholipid suspension (SEPS) was formulated using caprylocaproyl macrogol-8 glycerides (S)/ (lecithin/ propylene glycol) (

Solid dispersion systems have been widely used to enhance dissolution rate and oral bioavailability of poorly water-soluble drugs. However, the formulation process development and scale-up present a number of difficulties which has greatly limited their commercial applications. In this study, solid dispersions (SDs) of desloratadine (DSL) with povidone (PVP) and crospovidone (cPVP) were prepared by spray coating technique. The process involved the spray application of 96% ethanol solution of DSL and PVP/cPVP, and subsequent deposition of the coprecipitates onto microcrystalline cellulose pellets during drying by air flow in a mini spray coater. The results from the present study demonstrated that the spray coating process is efficient in preparing SDs with enhanced drug dissolution rate and it is highly efficient in organic solvent removal. Both PVP and cPVP greatly improved drug dissolution rate by SDs, with PVP showing better solubilization capability. Very fast drug dissolution rate is achieved from SDs containing PVP regardless of differences in K grade. SD with smaller particles of cPVP have higher drug dissolution rate in comparison to the cPVP with larger particles. Results from physical state characterization indicate that DSL in SDs exist in the amorphous (high free-energy) state which is probably stabilized by PVP/cPVP. After 6-month accelerated stability study, DSL remains amorphous, while PVP and cPVP act as anti-plasticizing agents, offering efficient steric hindrance for nucleation and crystal growth.