Mikronizacija dronedaron hidroklorida u spiralno strujnom mlinu

doctoral thesis

• Title (english): Micronization of dronedarone hydrochloride in a spiral jet mill
• Author: Šimo Kordić
• Mentor: Gordana Matijašić (mentor)
• Committee member: Krunoslav Žižek (predsjednik povjerenstva)
• Committee member: Igor Dejanović (član povjerenstva)
• Committee member: Mladen Brnčić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Chemical Engineering and Technology; Zagreb
• Defense date and country: 2018-05-11, Croatia
• Scientific / art field, discipline and subdiscipline: TECHNICAL SCIENCES; Chemical Engineering; Mechanical, Thermal and Separation Processes
• Universal decimal classification (UDC): 66 - Chemical technology. Chemical and related industries

Abstract

Dronedaron je relativno noviji lijek koji može smanjiti mogućnost hospitalizacije pacijenata s bolestima krvožilnog sustava, a posebno kod bolesnika koji imaju paroksizmalnu ili perzistentnu fibrilaciju atrija, sinusni ritam ili kardioverziju. Smatra se da će biti najbolji izbor za kontrolu ritma kod pacijenata s fibrilacijom atrija koji nemaju zapis o bolestima srca, bolesti koronarnih arterija i povišenog krvnog tlaka bez hipertrofije lijeve klijetke. Raspodjela veličina čestica farmaceutski aktivnih tvari uvelike određuje djelotvornost krajnjeg proizvoda. Da bi dobili finalni dozirni oblik željenih karakteristika često je potrebno aktivnu tvar dovesti u određeno stanje disperznosti. Sve veća potreba za farmaceutskim proizvodima direktno utječe na potražnju fino usitnjenih aktivnih tvari točno specificirane raspodjele veličina čestica. Većom kontrolom i užim specifikacijama gotovih proizvoda raste pritisak na proizvođače aktivnih tvari. Traže se aktivne tvari vrlo uskih raspodjela veličina čestica s minimalnim udjelom sitnih i krupnih veličinskih intervala. Spiralno strujni mlinovi se često koriste za mikronizaciju zbog mogućnosti sudara čestica pri velikim brzinama koja su rezultat velikih ubrzanja u struji fluida. Mikronizacija je termin koji se koristi pri opisivanju tehnološke operacije usitnjavanja koja rezultira s raspodjelom veličina čestica ispod 10 mm. Smanjenje veličine čestica proizlazi iz ubrzanja čestica tako da se usitnjavanje događa kao posljedica međusobnog sudara čestica. Uvjete provedbe usitnjavanja nije moguće predvidjeti samo na osnovu raspodjele veličina čestica polaznog materijala jer sam proces usitnjavanja značajno ovisi i o mehaničkim svojstvima materijala. Zato je optimizacija procesa usitnjavanja provedena eksperimentalnim putem te je razvijen teorijski pristup predviđanja optimalnih uvjeta usitnjavanja. Analiziran je utjecaj parametara spiralno strujnog mlina na fizikalne, kemijske, morfološke i strukturne značajke dronedaron hidroklorida. Mikronizacija dronedaron hidroklorida provedena je u laboratorijskom spiralno strujnom mlinu. Proveden je faktorski plan pokusa s tri varijable na tri razine te je napravljena statistička obrada dobivenih rezultata. Energetskim pristupom evaluacije procesa usitnjavanja prikazan je odnos između stupnja usitnjavanja i specifične energije usitnjavanja. Kinetičkim pristupom u analizi procesa usitnjavanja uključene su populacijske bilance te je istražena mogućnost predviđanja raspodjele veličina čestica usitnjenih uzoraka. Analizirane su fizikalno-kemijske i mehaničke karakteristike usitnjenog materijala s ciljem definiranja uvjeta koji daju materijal željenih svojstva za primjenu u gotovom dozirnom obliku.

Abstract (english)

Dronedarone is relatively a new drug which can lower chances of hospitalization in patients having cardiovascular diseases especially those with paroxysmal or persistent atrial fibrillation, having sinus rhythm, or patients likely to be cardioverted. Dronedarone belongs to the group of antiarrhythmic drugs and helps restore heart rhythm control. Antiarrhythmic are drugs that are used to treat abnormal heart rhythms like atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation. Dronedarone is considered best option for control of heart rhythm in atrial fibrillation patients having no record of heart disease, coronary artery disease and hypertension without left ventricular hypertrophy. Efficacy of final pharmaceutical product is greatly defined with particle size distribution of pharmaceutical active substance. To obtain final dosage form with specified characteristics it is often necessary to transform active substance in certain form of dispersity. Rising demand for pharmaceutical products directly influence on demand for fine grounded active substances with specified particle size distribution. Very narrow specifications and strict controls of finished products increases pressure on active substance producers. Narrow particle size distribution with minimum fraction of fines and minimum fraction of large particles is common condition for active substance. Possibility of high speed particle collisions as result of acceleration in fluid stream is reason why spiral jet mill is often used for micronisation of active substances. Micronisation is term used to describe technological operation of size reduction which results in particle size distribution below 10 mm. Particle size reduction is a result of particle acceleration and interparticle collision. Milling process greatly depends on mechanical properties of starting material and it is not possible to predict milling conditions just according to particle size distribution of starting material. Experimental milling process optimization was performed and theoretical approach for prediction of optimal milling condition was analyzed. Influence of process parameters on physical, chemical, morphological and structural properties of Dronedarone hydrochloride was investigated. Micronisation of Dronedarone hydrochloride was performed on laboratory spiral jet mill. Full factorial design with three factors on three levels was conducted and statistical analysis of obtained data was performed. Energy based approach was used for evaluation of milling process resulting with relationship between degree of micronisation and specific energy consumption. Kinetic approach included use of population balances and matrix solution to the milling process analysis which enabled investigation of prediction of particle size distribution after comminution. Physical, chemical and mechanical properties of micronized samples were used to define milling conditions to obtain desired material properties for use in final dosage form.

• Keywords: dronedaron hidroklorid; energetski pristup; faktorski plan pokusa; mikronizacija; populacijska bilanca; spiralno strujni mlin
• Keywords (english): dronedarone hydrochloride; energy based analysis; factorial design; micronisation; population balances; spiral jet mill
• Language: croatian
• URN:NBN: urn:nbn:hr:149:693747
• Promotion: 2023
• Study programme: Title: Chemical Engineering - Doctoral Course; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje tehničkih znanosti, polje kemijsko inženjerstvo (doktor/doktorica znanosti, područje tehničkih znanosti, polje kemijsko inženjerstvo)
• Type of resource: Text
• Extent: 187 str. ; 30 cm
• File origin: Born digital
• Access conditions: Open access
• Created on: 2023-08-30 11:14:35