Uporaba NIR spektroskopije za študij ključnih fizikalno-kemijskih parametrov nekaterih farmacevtskih oblik : doktorska disertacija

Marković, Snežana (avtor), Kerč, Janez (mentor)

NIR spektroskopija ima vse bolj ključno vlogo v farmacevtski industriji, tako na področju analize materialov kot pri spremljanju tehnoloških procesov. Metoda NIR omogoča hitro in enostavno izvedbo meritev, izvedbo meritev skozi ovojnino (steklo), spremljanje kemijskih in fizikalno-kemijskih lastnosti materiala, meritev vzorčnega materiala brez dodatne obdelave, kar omogoča neposredne medprocesne meritve (in-line), material pa ostane po meritvi nespremenjen. V nalogi smo predstavili možnosti uporabe NIR spektroskopije pri proučevanju različnih trdnih farmacevtskih oblik v različnih fazah procesa njihove izdelave. V raziskavo smo vključili naslednje farmacevtske oblike: kapsule, ki so vsebovale obložene pelete, obložene tablete in liofilizat. a) Kapsule z obloženimi peletami z gastrorezistentno oblogo Obloga na peletah in tabletah ima običajno neko specifično funkcijsko vlogo. Gastrorezistentna obloga zaščiti vsebino jedra pred želodčnim kislim medijem in omogoča sproščanje zdravilne učinkovine v nevtralnem in bazičnem mediju v črevesju. Pravilno sproščanje zdravilne učinkovine iz formulacije je odvisno od mnogih dejavnikov, kot so sestava jedra in obloge, vpliv karakteristik vhodnih materialov, kot so velikost delcev zdravilne učinkovine, ter parametrov farmacevtske oblike, kot so velikost pelet, debelina obloge, oblika tablete, itn. Pri proučevanju procesa izdelave kapsul z obloženimi peletami z gastrorezistentno oblogo smo v obširni raziskavi razvili in ovrednotili uporabo NIR metod za namen neposredne (in-line) kontrole kakovosti polizdelka, za napovedovanje kakovosti končnega izdelka ter za identifikacijo vplivov lastnosti vhodnih materialov, polizdelka in procesnih parametrov na kakovost končnega izdelka. V Poglavju 1 smo razvili NIR metode za neposredno (in-line) medprocesno spremljanje kritičnih parametrov v različnih stopnjah procesa izdelave. V stopnji sušenja peletnih jeder smo medprocesno spremljali vsebnost rezidualnih topil, v stopnji oblaganja peletnih jeder smo medprocesno spremljali kakovost nanosa obloge oziroma debelino obloge, poleg tega pa smo tudi spremljali velikost in porazdelitev velikosti delcev. V NIR spektrih so vsebovane informacije o lastnostih intermediatov, zato v NIR modelih praviloma uporabimo spektralna območja, v katerih so iskane lastnosti najbolj izražene. Z inovativnim pristopom statistične meta-analize, narejene na PLS utežeh zgrajenih NIR modelov za posamezne medprocesne parametre polizdelka in izdelka, smo ovrednotili, kolikšen delež informacij glede individualnih lastnosti polizdelkov so vsebovane v kompleksnem hierarhičnem NIR modelu kakovosti končnega izdelka (ustrezna acidorezistenca obloge), ki zajema spektralne podatke, zbrane tekom celotnega procesa. Takšna analiza pomaga pri razumevanju in kvantificiranju prispevkov posameznih parametrov in mehanizmov. Poglavitna značilnost modelov NIR je, da kvantificirajo korelacije med spremembami v spektru in v spremembi fizikalnih oziroma kemijskih lastnosti analiziranega vzorca. Za poglobljeno razumevanje vzročnosti opaženih korelacij smo proučevali vplive pogojev in procesnih parametrov, karakteristik vhodnih materialov, ter kakovosti polizdelka v različnih stopnjah procesa na kakovost končnega izdelka (omejeno na test acidorezistentnosti). Variabilnost kakovosti obloge (acidorezistenca obloge) smo raziskovali na dva komplementarna načina, in sicer s pomočjo multivariantnih statističnih metod procesne kontrole (MSPC) ter inovativno interprocesno NIR analizno metodo z vzorčenjem, ki temelji na vzorčevanju polizdelkov iz zaporednih procesnih korakov (Poglavje 2). Z MSPC smo korelirali vse zbrane vhodne parametre (proces, surovine, intermediati) in acidorezistenco obloge. V interprocesni NIR metodi pa smo z vzorčenjem polizdelkov identificirali procesne stopnje, kjer se pojavi največji vpliv na kakovost (pol-)izdelka. Primerjava obeh komplementarnih analiz omogoča v primerjavi s klasično statistično analizo globlji vpogled na procese in mehanizme, ki definirajo kakovost obloge. Predstavljena interprocesna NIR metoda temelji na dejstvu, da so v NIR spektru vsebovane kemijske in fizikalno-kemijske lastnosti materiala. Spektralna informacija iz posamezne stopnje, v kolikor je povezana z relevantnimi fizikalno-kemijskimi spremembami, lahko služi kot identifikacijski odtis stopnje procesa, kjer so se lastnosti materiala najbolj spremenile v korelaciji s kakovostjo izdelka. V predstavljeni raziskavi smo potrdili, da lahko že majhna sprememba v lastnostih vhodnih materialov (lastnosti laktoze) znatno vpliva na proces (iztiskanja in krogličenja) in posledično na kakovost acidorezistentnost obloge. Peletna jedra, pripravljena z laktozo novega dobavitelja 2, ki je imela rahlo različne lastnosti od prej uporabljene laktoze dobavitelja 1 in pripravljenih pri enakih procesnih pogojih iztiskanja in krogličenja, so nastale daljše pelete in imele krhkejšo strukturo, ki so se v nadaljnjih procesih lomile. Rezultati so bili potrjeni z dodatnimi raziskavami, kjer smo z analiziranjem debeline obloge potrdili neenakomerno debelino obloge, kar je bila posledica lomljenja pelet med oblaganjem in sušenjem obloženih pelet. Dodatna analiza NIR spektrov več serij laktoze je nakazala razliko v porazdelitvi velikosti delcev, kristaliničnosti in vsebnosti vezane vode v laktozi novega dobavitelja 2. Prednost interprocesne NIR analizne metode vzorčenja polizdelkov je v primerjavi s klasično MSPC metodologijo predvsem v tem, da je enostavna in hitro izvedljiva. Analize se lahko izvajajo tudi z laboratorijskim NIR spektrometrom, s čemer se lahko izognemo nakupu dragih industrijskih spektroskopskih aparatov. Predstavljena interprocesna NIR analizna metoda vzorčenja polizdelkov ima velik potencial pri hitremu odkrivanju virov variabilnosti, izboljšavi kakovosti produktov, in povečanju ekonomičnosti procesov (skupen imenovalec vseh naštetih ciljev je redukcija variabilnosti). Obložene tablete V raziskavi obloženih tablet v Poglavju 3 smo proučevali vpliv sestave jedra in obloge na kinetiko sproščanja zdravilne učinkovine iz farmacevtske oblike. Pri izbrani formulaciji je imela obloga funkcijo gastrorezistentne zaščite zdravilne učinkovine v tableti. S sistematičnim pristopom ovrednotenja načrtovanja z vgrajeno kakovostjo (QbD) smo pripravili vzorce z različno sestavo tako, da so bile količine pomožnih snovi v tableti na skrajnih mejah zastavljenega področja načrtovanja (DoE). Ugotovili smo, da spremembe količine pomožnih snovi (premreženi povidon, etanol in delno razmerje Eudragit/etilceluloza) vplivajo na absorpcijo v NIR območju. Preverili smo, če je možno s pomočjo teh spektralnih sprememb napovedovati parametre, ki vplivajo na kakovost obloge ter hitrost sproščanja zdravilne učinkovine iz končne formulacije. Premreženi povidon, ki se nahaja v jedru, se izraža v transmisijskem NIR spektru v območju od 11500 do 9000 in od 8800 do 7600 cm-1. Razmerje Eudragit-a in etilceluloze ima velik vpliv na profil raztapljanja obložene tablete, vendar se sprememba razmerja Eudragit/etilceluloza odraža v NIR absorpciji le, kadar je obloga pripravljena z gostejšo koncentracijo raztopine za oblaganje. Količina etanola v suspenziji močno vpliva na strukturo obloge, prav tako pa tudi na NIR absorpcijo v območjih od 8200 do 7200, od 6900 do 6100, od 5950 do 5300 in od 4450 do 4300 cm-1. Razlike v količini kalcijevega stearata, ki verjetno zaradi hidrofobnosti v manjši meri vpliva na raztapljanje, ne vplivajo na absorpcijo v NIR območju. NIR analiza QbD vzorcev pripravljenih na skrajnih mejah zastavljenega področja načrtovanja, podajo informacije, kako sprememba količine pomožnih snovi vpliva na NIR absorpcijo, in tudi kako dobro lahko napovemo kakovost izdelka. V našem primeru ne moremo zagotovo potrditi, da lahko izgradimo natančen in kakovostnem NIR model za določanje sproščanje zdravilne učinkovine iz formulacije, saj nekatere spremembe pomožnih snovi ne vplivajo na absorpcijo v NIR valovnem območju. Na sproščanje zdravilne učinkovine ima velik vpliv sestava in priprava obloge, največji vpliv imata razmerje Eudragit/etilceluloza in količina etanola pri pripravi obloge. Določeni vplivi se ne zaznajo dobro z NIR spektroskopijo, kot na primer spremembe razmerja Eudragit/etilceluloza v oblogi so opazne v NIR spektru le kadar je pripravljena z redkejšo suspenzijo (več etanola). c) Intermolekularne vezi v liofilizirani farmacevtski obliki V poglavju 4 smo dokazali obstoj intermolekularne vezi med zdravilno učinkovino in pomožno snovjo (manitolom) v liofiliziranem produktu. Intermolekularna vez med zdravilno učinkovino in manitolom se v raztopini tvori zelo hitro, kar smo lahko dokazali s standardno NMR spektroskopijo. Med procesom liofilizacije se iz formulacije odstrani topilo, intermolekularna vez med zdravilno učinkovino in manitolom bi se naj med tem procesom ohranila in s tem posredno stabilizirala zdravilno učinkovino v farmacevtski obliki. Pri dokazovanju intermolekularne vezi v končnem liofilizatu so se standardne analizne metode izkazale kot neuspešne. Z uporabo NIR in RAMAN spektroskopije pa smo uspešno potrdili intermolekularno estersko vez med zdravilno učinkovino in manitolom v strukturi liofilizirane pogače. Razvita NIR analizna metoda je bila edina, s katero smo lahko kvantitativno določili razmerje vezane zdravilne učinkovine v liofilizirani formulaciji in proste zdravilne učinkovine v zmesi, ki je bila kasneje dodana v liofiliziran izdelek. Pri naših raziskavah se je NIR metoda uspešno izkazala za kvalitativno in kvantitativno določevanje ključnih kritičnih parametrov vhodnih materialov, polizdelkov in izdelkov ter kritičnih procesnih parametrov. Predstavljene NIR analizne tehnike in pristopi v prihodnosti razširjajo možnosti uporabe NIR spektroskopije za raziskovanja lastnosti in procesnih parametrov izdelave farmacevtskih izdelkov.

• Jezik: Slovenski jezik
• Ključne besede: trdne farmacevtske oblike, tehnološki procesi, fizikalno-kemijske lastnosti, kapsule, obložene tablete, liofilizat, zdravilne učinkovine, sproščanje
• Vrsta gradiva: Doktorska disertacija
• Tipologija: 2.08 - Doktorska disertacija
• Organizacija: FFA - Fakulteta za farmacijo
• Kraj izida: Ljubljana
• Založnik: [S. Marković]
• Leto izida: 2017
• Št. strani: III f., 161 str.
• PID: 20.500.12556/RUL-137415
• UDK: 661.12:615.453(043.3)
• COBISS.SI-ID: 290019584
• Datum objave v RUL: 16.06.2022

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Use of NIR spectroscopy for study of key physico-chemical attributes of selected pharmaceutical dosage forms

Izvleček

In the pharmaceutical industry, the NIR spectrometry has essential role in analysis of material and in monitoring of manufacturing process. NIR method is quickly performed in less than a minute and enables multi-component analysis. Chemical and physico-chemical information of material are contained in NIR spectrum. For analysis, the sample material doesn’t need any special pretreatment and after analysis the material remains unchanged. The NIR analysis could be performed through the container and could be performed in-line in various processes In the thesis the potential use of the NIR spectroscopic methods for investigation of different pharmaceutical dosage forms in various stages of their manufacturing process has been studied. Three different pharmaceutical dosage forms; the capsule with coated pellets, the coated tablets, and lyophilisate have been investigated. a) The capsule with gastroresistant coated pellets The coating on the pellets and tablets generally has a specific function. The enteric coating has the important task to protect the core content from gastric acidic media and enables the release of the active ingredient in the neutral and alkaline medium in the intestine. The proper release of active ingredient from the formulation depends on numerous factors, such as particle size distribution of API and parameters of pharmaceutical dosage form, such as particle size of pellets core, the coating thickness, etc. The research of the preparation process of the coated pellets with gastroresistant coating has been extensively investigated and evaluated the possible uses of NIR techniques: for in-line control of intermediate, for prediction of final quality of product and for investigation of the influences of characteristics of the raw materials, intermediate and process parameters on final quality of the product. In Chapter 1 NIR technique has been directly introduced for in-line monitoring of the key parameters in different process steps of the production. In the drying process step of the pellets’ cores we have monitored the coating thicknesses or controlled appliance of content of the coating solution on the pellets, the content of residual solvent in the coating process step was monitored, and additionally the particle size distribution during the coating was monitored. The characteristics of intermediate material are contained in the NIR spectra, the spectral ranges in NIR model are generally used, which contain the most information about the measured characteristics. With the new innovative statistical approach of meta-analysis, which is made of PLS individual loading of interprocess NIR model, we evaluated the impact of the individual studied parameters of process intermediate that are included in complex hierarchical NIR model for final quality of the product (acid resistance of coat), where the spectral information collected during the process are included in model. This analysis enhances the understanding and quantification contributions of individual parameters and process mechanisms. Furthermore, in Chapter 2 we have investigated the impact of process parameters, process conditions, characteristics of the raw materials and quality of intermediates at various stages of the process on the fluctuations of the product quality (limited to acid resistance of pellet coating test). The fluctuation of the product quality was investigated by two complementary methods: the MSPC statistical methods and the new customized interprocess NIR sampling analytical method, which is based on sampling process of intermediates after sequential process steps. With MSPC method we have correlated the huge amount of process data, raw material and intermediate information data to acid resistance of pellet coating. With interprocess NIR sampling method of process intermediate the process step which had the most impact on quality of intermediate was determined. The comparison of both analytical methods enables border insight on process and mechanisms that define the coating quality in comparison to classical statistical analysis. The NIR intermediate sampling method is based on the fact that the chemical and physical-chemical information of material are contained in the NIR spectra. If the spectral information of intermediate at individual process stage correlate with relevant physico-chemical changes, it can assist determination as fingerprint identification of process step, in which the properties of intermediates have changed the most in correlation to the product quality. In investigation it was confirmed that even small changes in the raw material properties (lactose characteristics) could have huge impact on the process (extrusion and spheronization) and the quality of final product (acidoresistance of coating). The pellets’ core prepared by lactose of supplier 2 with slightly different characteristics than before used lactose of supplier 1 under unchanged process conditions of extrusion and spheronization, longer and more frangible pellets’ core were formed which have broken during the further process steps. The results were confirmed with additional analysis, the analysis of coat thickness confirmed unevenness of coating thickness which consequently led to broken pellets during the further coating and drying process steps. Additionally broader analysis of NIR spectra of lactose of larger number of batches have indicated that differences in particle size distribution, crystallinity and the content of residual bonded water in new lactose of supplier 2. The new interprocess NIR intermediate sampling method has advantage compared to classical MSPC methodology particularly because it is practical, easily and quickly to perform. Also analysis can be made by off-line laboratory NIR spectrometer thereby avoiding purchase of expensive industrial spectroscopic devices. The introduced interprocess NIR intermediate sampling method has a great potential in quicker identifying sources of variability and to improve the quality of products and increase the economic efficiency of processes (the aim of these methods is the reduction of variability). b) Coated tablets In the study of coated tablets in Chapter 3 the influence of the composition of the core and the film coating on the release of active pharmaceutical ingredient from the coated tablet formulation was investigated. By systematic QbD (quality by design) approach the samples with parameter values of excipients at the edge limits of the design space of the tablet formulation were prepared. The different content of excipient (crosslinked povidone, ethanol, and partly ratio Eudragit/ethyl cellulose) effect the NIR absorption. It was verified if these NIR absorption changes could predict parameters that have influence on the quality of acid resistance of the film coating and the drug release from the coated tablet. Crosslinked povidone in tablet core was detected in ranges from 11500 to 9000 and from 8800 to 7600 cm-1 in NIR transmission spectra. The ratio of polymers Eudragit and ethyl cellulose has large influence on dissolution profile of coated tablet, but influence of the ratio of polymers could be detected in NIR absorption spectra only if the coating was prepared by the denser coating suspension. The quantity of ethanol in suspension had substantially influenced on coat structure and also on NIR absorption in the range from 8200 to 7200, from 6900 to 6100, from 5950 to 5300 and from 4450 to 4300 cm-1. The calcium stearate which had minor influence on dissolution profile, probably through hydrophobicity, unfortunately on NIR absorption had no effect. The content of crosslinked povidone, Eudragit, ethyl cellulose and the amount of ethanol in coating solution had the significant impact on the dissolution profile which could be well detected by NIR spectroscopy. QbD samples made at the edge limits of design space could provide the information how the changes of the content of excipient influence the NIR absorption, and provide information how good the NIR model predicts the product quality. In our case it cannot be confirmed that an accurate and good NIR model can be built to predict API release from formulation, because some changes in the amount of excipients have not effect on absorption in the NIR wavelength range. The structure and preparation of tablet coating have great influence on API release from formulation, however, the ratio Eudragit/ethyl cellulose and the amount of ethanol have the greatest influence on preparation of coating formulation. Certain influences cannot be well detected with NIR spectroscopy like the change in ratio of Eudragit/ethyl cellulose in the coating are observed in NIR absorption only when the coating suspension is prepared with lower amount of ethanol. c) The study of intermolecular bonds in a lyophilisate In Chapter 4 the existence of the intermolecular bond between the active ingredient and excipient (mannitol) in the lyophilized product was determined with NIR spectroscopy. The intermolecular bond between the active ingredient and mannitol is quickly formed in lyophilisation solution, which was successfully confirmed with standard NMR analysis. During the process of lyophilisation the solvent is removed from the formulation, the intermolecular bond might maintain and consequently stabilize the active ingredient in the pharmaceutical dosage form, which could not be determinate with the standard analytical methods. The NIR and RAMAN techniques were able to confirm intermolecular ester bond between active ingredient and mannitol in lyophilized product, and the NIR technique was the only method, which was able to quantitatively determine the ratio of bonded active ingredient in lyophilized formulation and free active ingredient added later to lyophilized product. In all the research the NIR method has been successfully applied for the qualitative and quantitative determination of key critical parameters of the incoming materials, intermediate products, products and critical process parameters. In the future the presented NIR technique and methods can extend the use of NIR spectroscopy for investigating the properties and manufacturing process parameters of pharmaceutical dosage form.