This work of thesis aims to validate three gas chromatographic methods for the determination of the potential impurities of the EVA polymer [Poly (Ethylene-co-Vinyl Acetate)] in Buprenorphine HCl implant. The first method concerns the validation of vinyl acetate, the second concerns ethylene and the third the additives. Buprenorphine HCl implants are flexible sticks made of polymer and active principle (buprenorphine derived from opioids, used to treat opioid addiction). The studied implants are designed to be introduced under the skin to ensure gradual release of the drug over a six-month period. This new formulation is slowly replacing the classic therapy via sublingual tablets since it helps to prevent potential problems related to intentional overdose. Therefore, the gradual release implants represent a useful alternative to counter the very widespread problem of opioid addiction. Buprenorphine is used because, unlike other opioids, it guarantees a lower probability of developing addiction. On the other hand, EVA, a copolymer consisting of vinyl acetate and ethylene, has received the approval of the food and drug administration (FDA) for its use in medical devices because it has appeared to be a non-toxic and insoluble biocompatible material. Among the impurities of the EVA, in addition to vinyl acetate and ethylene, several additives such as 2,6-di-tert-butyl-4-methylphenol [BHT], 3,5 -di-tert-butyl-4-hydroxybenzaldehyde [3,5-DTHBA or DTBHB], 2,6-di-tert-butyl-4-ethylphenol [BEHT or BHEB], erucamide (cis-13-docosenamide) [ERMD] and irganox 1076 (octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionate) [IRG-1076] can be found. These molecules are added to prevent the polymer degradation by acting as a free radical scavenger. It is therefore important to have a validated method capable of giving statistically reliable results for the determination of these impurities. In this validation, the parameters of linearity, accuracy, repeatability, limit of quantification and specificity were evaluated using a solution that emulated implant composition (mixture of the grinded polymer and buprenorphine). This rebuilt implant has been used for the entire process of the validation to ensure less costs for the laboratory. Accordingly, to what has been said, the results obtained with this validation confirmed that the method can be considered validated and suitable for its purpose.
In questo lavoro di tesi sono stati validati tre metodi gascromatografici per la determinazione delle potenziali impurezze del polimero EVA [Poly(Ethylene-co-Vinyl Acetate)], in impianti di buprenorfina HCl utilizzati nella terapia della dipendenza da oppioidi. Il primo metodo riguarda la validazione del vinil acetato, il secondo riguarda l’etilene e il terzo gli additivi. Gli impianti di buprenorfina sono bastoncini flessibili costituiti dal principio attivo (buprenorfina derivato degli oppioidi) e il polimero estrusi a caldo. Sono stati progettati per essere applicati sottocute e garantire un rilascio graduale del farmaco in un arco di tempo di sei mesi. Tra le impurezze dell’EVA da determinare vi sono vinil acetato ed etilene, ovvero i monomeri costituenti del co-polimero e additivi per impedirne la degradazione tra cui: 2,6-di-tert-butil-4-metilfenolo [BHT], 3,5-di-tert-butil-4-idrossibenzaldeide [3,5-DTHBA or DTBHB], 2,6-di-tert-butil-4-etilfenolo [BEHT or BHEB], erucamide (cis-13-docosenamide) [ERMD], irganox 1076 (ottadecil-3-(3,5-di-tert-butil-4-idrossifenile)-propionato) [IRG-1076]. Per quanto riguarda la parte strumentale gli analiti vinil acetato ed etilene sono stati analizzati tramite gascromatografia per spazio di testa, perché hanno alte tensioni di vapore. Questa tecnica rende più semplice e rapida la fase di preparazione del campione. Gli additivi invece, presentano bassi valori di tensione di vapore per questo motivo sono stati analizzati per iniezione diretta. In entrambi i casi il detector utilizzato è il FID. Nella validazione dei metodi sono stati valutati i parametri di linearità, accuratezza, ripetibilità, limite di quantificazione e specificità, attraverso l’utilizzo di una miscela di impianto ricostruito, che emula la composizione dell’impianto di buprenorfina HCl (per impianto ricostruito si intende una miscela del polimero triturato e buprenorfina) ed è stato utilizzato per l’intero processo di convalida per garantire minori costi per il laboratorio. I risultati ottenuti dalla validazione indicano che il metodo utilizzato risulta accurato, specifico e adeguato allo scopo.
Validazione di metodi Gas Cromatografici per la determinazione di potenziali impurezze dovute al polimero EVA [Poly(Ethylene-co-Vinyl Acetate)] in impianti sottocutanei per il rilascio graduale di Buprenorfina HCl
CALICCHIO, NICOLETTA ANNA
2019/2020
Abstract
This work of thesis aims to validate three gas chromatographic methods for the determination of the potential impurities of the EVA polymer [Poly (Ethylene-co-Vinyl Acetate)] in Buprenorphine HCl implant. The first method concerns the validation of vinyl acetate, the second concerns ethylene and the third the additives. Buprenorphine HCl implants are flexible sticks made of polymer and active principle (buprenorphine derived from opioids, used to treat opioid addiction). The studied implants are designed to be introduced under the skin to ensure gradual release of the drug over a six-month period. This new formulation is slowly replacing the classic therapy via sublingual tablets since it helps to prevent potential problems related to intentional overdose. Therefore, the gradual release implants represent a useful alternative to counter the very widespread problem of opioid addiction. Buprenorphine is used because, unlike other opioids, it guarantees a lower probability of developing addiction. On the other hand, EVA, a copolymer consisting of vinyl acetate and ethylene, has received the approval of the food and drug administration (FDA) for its use in medical devices because it has appeared to be a non-toxic and insoluble biocompatible material. Among the impurities of the EVA, in addition to vinyl acetate and ethylene, several additives such as 2,6-di-tert-butyl-4-methylphenol [BHT], 3,5 -di-tert-butyl-4-hydroxybenzaldehyde [3,5-DTHBA or DTBHB], 2,6-di-tert-butyl-4-ethylphenol [BEHT or BHEB], erucamide (cis-13-docosenamide) [ERMD] and irganox 1076 (octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionate) [IRG-1076] can be found. These molecules are added to prevent the polymer degradation by acting as a free radical scavenger. It is therefore important to have a validated method capable of giving statistically reliable results for the determination of these impurities. In this validation, the parameters of linearity, accuracy, repeatability, limit of quantification and specificity were evaluated using a solution that emulated implant composition (mixture of the grinded polymer and buprenorphine). This rebuilt implant has been used for the entire process of the validation to ensure less costs for the laboratory. Accordingly, to what has been said, the results obtained with this validation confirmed that the method can be considered validated and suitable for its purpose.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/11827