Pharmaceutical development of enteric-coated pellets by application of quality by design concept and artificial intelligence techniques

Cilj ovog istraživanja je postizanje višeg stepena znanja o proizvodnji gastrorezistentnih peleta i unapređenje farmaceutskog razvoja gastrorezistentnih peleta primenom koncepta dizajna kvaliteta i različitih tehnika veštačke inteligencije. Istraživanje se sastoji iz tri dela. U prvom delu istraživanja je postavljen ciljani profil kvaliteta gastrorezistentnih peleta kao međuproizvoda koji se koristi za punjenje tvrdih želatinskih kapsula i identifikovani su njegovi kritični atributi kvaliteta. Tehnikom preliminarne analize opasnosti izvršena je analiza rizika za ispitivanje uticaja različitih tehnika proizvodnje peleta na kritične atribute kvaliteta gastrorezistentnih peleta sa duloksetin hidrohloridom kao model supstancom. Ispitane su sledeće tehnike oblaganja inaktivnih peleta duloksetin hidrohloridom: oblaganje peleta praškom (suvo oblaganje), oblaganje aktivnom supstancom iz rastvora i oblaganje iz supstancom. Tehnike oblaganja peleta gastrorezistentnim filmom koje su ispitane su: oblaganje praškom i oblaganje suspenzijom za oblaganje u kojoj je gastrorezistentni polimer rastvoren. Rezultati analize slika peleta sa optičkog mikroskopa i skenirajućeg elektronskog mikroskopa pokazale su da pelete proizvedene tehnikom suvog oblaganja poseduju lošije morfološke karakteristike u odnosu na pelete proizvedene tehnikama u kojima je tečnost korišćena kao vehikulum za aktivnu supstancu jer doziranje praška na pelete nije tako uniformno kao doziranje tečnosti. Obe ispitane tehnike oblaganja peleta gastrorezistentnim filmom omogućile se postizanje specificirane gastrorezistencije od ne više od 10% oslobođenog duloksetina u kiseloj fazi testa ispitivanja brzine rastvaranja. Za postizanje slične gastrorezistencije bio je potreban 20% veći nanos filma kada se film nanosio suvim oblaganjem zbog veće permeabilnosti ovog filma. Sve tri ispitane formulacije su pokazale potpuno oslobađanje duloksetima u fazi testa ispitivanja brzine rastvaranja koja se izvodi u fosfatnom puferu pH 6.8, ali su postojale razlike u obliku kriva brzine rastvaranja između formulacija. Najsporije oslobađanje imala je formulacija proizvedena tehnikom suvog oblaganja što je uslovljeno prisustvom lipofilnog plastifikatora – ricinusovog ulja u formulaciji i većom debljinom gastrorezistentnog filma. Dugoročna stabilnost gastrorezistentnih peleta praćena je određivanjem sadržaja srodnih supstanci duloksetina nakon 12, 24 i 36 meseci čuvanja u ambijentalnim uslovima. Nakon 36 meseci, u formulaciji proizvedenoj tehnikom oblaganja rastvorenog duloksetina zabeležen je sadržaj degradacionog proizvoda 1-naftol od 0.57% što je iznad gornje dozvoljene granice za specificirane identifikovane nečistoće od 0.2%. Porast proizvoda hidrolize duloksetina je uzrokovan prisustvom amorfnog duloksetina u ovoj formulaciji čiji je nastanak u toku proizvodnog procesa dokazan DSC analizama u drugom delu istraživanja. Cilj drugog dela istraživanja je ispitivanje uticaja formulacijskih i procesnih parametara oblaganja peleta aktivnom supstancom na efikasnost procesa i koristan prinos proizvodnog procesa i definisanje prostora za dizajn u kome je omogućeno istovremeno postizanje postavljenih kriterijuma za izlaze koji su praćeni. U skrining fazi je korišćenjem frakcionog faktorijalnog dizajna tipa 28-4 ispitan uticaj karakteristika formulacije i parametara proizvodnog procesa na efikasnost i koristan prinos procesa oblaganja peleta duloksetin hidrohloridom. Rezultati skrining faze su objašnjeni DSC analizama koje su pokazale da u toku oblaganja peleta rastvorenim duloksetin hidrohloridom nastaje amorfni duloksetin sa temperaturom bliskoj temperaturama proizvoda u toku procesa proizvodnje...The aim of this research was to enhance the knowledge of production of enteric-coated pellets and to improve the pharmaceutical development of enteric-coated pellets by using quality by design concept and different techniques of artificial intelligence. The research comprises three parts. In the first part of the research, quality target product profile of enteric-coated pellets, as an intermediate to be filled in hard gelatine capsules, was set and critical quality attributes were identified. Preliminary hazard analysis technique was applied for analyzing the risk of using different techniques of production of coated pellets with respect to critical quality attributes of enteric-coated pellets that contain duloxetine hydrochloride as a model substance. Following drug layering techniques were examined: powder layering, solution layering and suspension layering. Following enteric-coating techniques were examined: dry coating and spray coating of suspension containing dissolved enteric-coating polymer. Results of analyses of images made by optical microscope and scanning electron microscope showed that pellets produced by dry coating have worse morphological features in comparison with pellets whose production involved using liquid as a vehicle for transportation of drug to pellets because dosing of powder during the coating was not as uniform as the dosing of liquids. Both examined techniques of enteric-coating of pellets enabled achieving specified gastric-resistance of not more than 10% of duloxetine being released in the acid stage of the dissolution test. Owing to higher permeability of films obtained by dry coating, 20% higher weight gain of enteric-coating was required to achieve gastric-resistance that was similar to the gastric-resistance of spray coated pellets. All of the three examined formulation showed complete release of duloxetine in the buffer stage of the dissolution test, but there were differences in the shape of the release curves. Dry coated pellets showed the slowest release rate that was caused by the presence of lipofilic plasticizer – castor oil in the formulation and thickness of the enteric-coating. Long term stability of enteric-coated pellets was assessed on account of level of impurities in pellets after 12, 24 and 36 months. After 36 months, solution layered pellets contained 0.57% of 1-naphthol which was above the upper qualification limit for specified identified impurities of 0.2%. Increase in the level of this product of duloxetine hydrolysis was caused by the presence of amorphous duloxetine in this formulation which was confirmed by DSC analyses in the second part of the research. The aim of the second part of the research was to evaluate effects of formulation characteristics and process parameters of drug layering process and to set the design space which allows for achieving all the criteria set for the predifined responses. Fractional factorial design 28-4 was used in the screening phase to evaluate the effect of formulation and process factors on efficiency and useful yield of pellets layering by duloxetine hydrochloride. Some of the results of the screening phase were explained by DSC analyses that showed that during the solution layering process amorphous duloxetine is formed and that its Tg is close to the product temperature during the coating process. In the optimization phase, central composite design and the response surface methodology were employed to examine the effect of level of hypromellose 6 cp and level of dry substances in the coating suspension on coating efficiency, useful yield, viscosity of coating suspension and process time..