Vrednotenje uporabnosti orodij procesne analizne tehnologije pri spremljanju filmskega oblaganja pelet

doktorska disertacija

Klemen Korasa (Author), Franc Vrečer (Mentor)

Abstract

Razvoj sodobnih farmacevtskih oblik in kompleksnih tehnoloških procesov je v začetku 21. stoletja vodil tudi do hitrega razvoja tehnologij in sistemov za obvladovanje proizvodnje zdravil. Sistem za načrtovanje, analizo in kontrolo proizvodnje, ki s pomočjo medprocesnih meritev kritičnih lastnosti materialov in procesnih parametrov zagotavlja končno kakovost izdelka, je v farmacevtski industriji znan pod imenom procesna analizna tehnologija oz. PAT. PAT sestavljajo različna orodja, kot so statistični in matematični pristopi za obdelavo podatkov, procesni analizatorji, sistemi za kontrolo procesov in pristopi za učinkovito obvladovanje znanja. V doktorski disertaciji smo največ pozornosti namenili študiju uporabnosti različnih procesnih analizatorjev za spremljanje in kontrolo procesa filmskega oblaganja pelet. Pri tem smo se v prvi vrsti osredotočili na bližnjo infrardečo (NIR) spektroskopijo, ki je tudi sicer najpogosteje uporabljen pristop za spremljanje procesa oblaganje pelet v realnem času. V drugem delu naloge smo ovrednotili uporabnost druge spektroskopske tehnike za merjenje ključnih karakteristik pelet – ramanske spektroskopije. Vzporedno smo preverili možnost uporabe dveh različnih tehnik za merjenje velikostnih atributov pelet med procesom oblaganja – tehnike prostorskega filtriranja (SFT) in slikovne analize delcev. Za doseganje čim večje vrednosti zajetih podatkov smo si pomagali z multivariatno analizo podatkov. Temelj doktorske disertacije predstavljajo štirje članki, katere smo objavili v priznanih znanstvenih publikacijah. Prvo objavljeno delo je pregledni članek, v katerem predstavimo različne možnosti spremljanja procesa oblaganja trdnih farmacevtskih oblik v realnem času. Po številu znanstvenih objav in posledično po številu vrednotenih atributov najbolj izstopa NIR spektroskopija, saj obstajajo številne objave, ki potrjujejo njeno uporabnost tako med procesom filmskega oblaganja tablet kot pelet. Zelo pogosto se v literaturi omenja tudi ramanska spektroskopija, ki pa se za razliko od NIR spektroskopije bistveno manj pogosto omenja kot orodje za spremljanje procesa oblaganja pelet. Obe metodi lahko opredelimo kot idealna PAT analizatorja, saj lahko iz posnetih spektralnih podatkov s postavitvijo multivariatnih modelov vrednotimo številne atribute kakovosti obloženih farmacevtskih oblik, kot so debelina obloge, količina nanosa obloge, vsebnost zdravilne učinkovine in hitrost sproščanja zdravilne učinkovine. Glede na teoretično ozadje je ramanska spektroskopija v primerjavi z NIR spektroskopijo manj primerna za merjenje polarnih molekul. Tako se v objavah, ki govorijo o določitvi vsebnosti vode med procesom oblaganja, omenja predvsem NIR sprektroskopija. V primeru obeh tehnik pa je slabo raziskano področje spremljanja temperiranja filmskih oblog. Drugo skupino procesno analiznih metod predstavljajo tehnike za direktno meritev debeline obloge (teraherčno pulzno slikanje ali TPI) ali velikosti delca (pristopi za merjenje dolžine tetive delca in slikovna analiza delcev). Njihovo uporabnost potrjujejo številne objave, vsi pristopi se ravno tako že uporabljajo v farmacevtski industriji, saj so tovrstne naprave že komercialno dostopne. Poleg zgoraj naštetih že uveljavljenih PAT orodij se vse bolj omenjajo številni novi pristopi, ki bi se lahko uveljavili v prihodnosti: optična koherenčna tomografija, akustična emisija, mikrovalovna resonanca in lasersko inducirana plazemska spektroskopija. V prvem raziskovalnem članku smo preučevali uporabnost SFT sonde za vrednotenje velikosti delcev ter NIR spektroskopije za določanje vsebnosti vode in debeline filmske obloge v realnem času. SFT sonda se je izkazala kot učinkovito sredstvo za spremljanje procesa oblaganja, ki je zaznala višjo hitrost rasti pelet ob vsakem povečanju hitrosti razprševanja oblagalne disperzije. Poleg tega je izmerjena velikost delcev zelo dobro korelirala z referenčnima metodama sejalne analize in statične slikovne analize. Največja slabost SFT-ja je bila nezmožnost detekcije pojava aglomeracije, saj meritve niso korelirale s številom dejanskih aglomeratov. Zanimivi so tudi izsledki vrednotenja procesa oblaganja pelet z NIR sondo. Spektri, posneti med oblaganjem pelet, so zelo dobro korelirali z referenčnima metodama izgube pri sušenju (LOD) in Karl Fischer titracije (KF), postavljeni multivariantni modeli pa so omogočali napoved vsebnosti vode tudi v peletah s spremenjeno kvalitativno sestavo obloge – drugi tip polimetakrilatnega polimera. Ravno tako se je NIR sonda dobro obnesla pri vrednotenju debeline obloge med procesom oblaganja. Model, postavljen na spektralnem območju izven vrhov vode, je učinkovito napovedal debelino obloge pelet med oblaganjem neodvisne serije. Poleg tega so NIR spektri zelo dobro korelirali s padanjem debeline obloge pelet v primeru pojava krušenja pelet. Rezultati dobro ponazarjajo širok spekter uporabnosti tovrstnih orodij med procesom oblaganja. Raziskavo NIR spektroskopije smo z drugim raziskovalnim člankom razširili na možnost vrednotenja procesa temperiranja obloge s podaljšanim sproščanjem. Za razliko od prvega dela raziskav, predstavljenega zgoraj, kjer smo NIR spektre snemali v napravi (»in-line«), smo tokrat spektre pelet snemali ob napravi (»at-line«). Ugotovili smo, da NIR spektri različno temperiranih vzorcev korelirajo z upadanjem intenzitete vrhov komponent, prisotnih pod filmsko oblogo s podaljšanim sproščanjem. Sklepali smo, da je nižanje intenzitete teh vrhov posledica prepletanja polimernih verig in koalescence polimernih delcev. Uporabnost pristopa smo preverili tako, da smo spektralne podatke umerili s podatki sproščanja zdravilne učinkovine ter nato model uporabili za napoved hitrosti sproščanja zdravilne učinkovine neodvisnih vzorcev v treh časovnih točkah. Z izjemo vzorcev, ki so imeli zelo visoko vsebnost vode (višja od 4,5 %), so se napovedane vrednosti dobro ujemale z dejansko hitrostjo sproščanja zdravilne učinkovine. Slabša napovedna moč modela v primeru vzorcev z visoko vsebnostjo vode je bila najverjetneje posledica direktnega vpliva vode na spektralne podatke ali posrednega vpliva preko spremembe strukture filmske obloge. Poleg tega smo v tej raziskavi ponovno potrdili uporabnost NIR spektroskopije za merjenje debeline filmske obloge pelet, kar je dodatno podkrepilo zaključke študije, predstavljene v zgornjem odstavku. Zgornjim zaključkom vrednotenja procesa temperiranja pelet daje dodano vrednost tudi dejstvo, da gre za prvo tovrstno objavljeno raziskavo. V zadnjem raziskovalnem članku smo predstavili možnost umeritve modela za spremljanje vsebnosti vode in debeline filmske obloge pelet v realnem času v napravi (»in-line«) z merjenjem NIR spektrov laboratorijskih vzorcev izven naprave (»off-line«). Učinkovitost predstavljenega pristopa, ki lahko močno zniža vložek v kalibracijo modelov za spremljanje procesa v napravi, smo potrdili z napovedjo debeline obloge in vsebnosti vode na treh neodvisnih pilotnih serijah. Sledila je obširna študija uporabnosti ramanske spektroskopije za spremljanje procesa oblaganja pelet, s katero smo vrednotili tako analizator za merjenje spektrov ob napravi (»at-line«) kot analizator za analizo procesa v napravi. Izsledki vrednotenja »at-line« procesnega analizatorja so pokazali, da je ramanska spektroskopija zelo učinkovito orodje za vrednotenje debeline obloge pelet in da, nekoliko presenetljivo, omogoča tudi solidno oceno vsebnosti vode v peletah. Z vsebnostjo vode v peletah sicer niso korelirali spektri, posneti z »in-line« različico ramanskega analizatorja, ki pa je omogočal točno in natančno napoved debeline obloge in količine razpršene disperzije med procesom oblaganja pelet. Z merjenjem ramanskih spektrov izven naprave in poskusom napovedi atributov pelet iz spektrov, izmerjenih v napravi, smo pokazali, da bi lahko zgoraj predstavljeni pristop umerjanja NIR modelov uporabili tudi v primeru ramanske spektroskopije. V okviru te študije smo na treh pilotnih serijah oblaganja pelet vrednotili tudi robustnost slikovne analize za merjenje debeline obloge pelet v realnem času. V napravi izmerjeni velikostni parametri so bili skladni s potekom procesa, kar smo med drugim potrdili s primerjavo meritev z metodo dinamične slikovne analize, ki je pokazala, da med obema metodama ni bistvenih razlik v izmerjeni debelini obloge. V doktorski disertaciji smo opravili obširno vrednotenje kar štirih različnih procesnih analizatorjev. Izsledki predstavljajo dopolnitev že obstoječega znanja uporabe PAT orodij in hkrati ponujajo nekatere vidike, ki pred tem še niso bili raziskani v obstoječih znanstvenih objavah. Predstavljena vsebina lahko tako pripomore k hitrejši in učinkovitejši implementaciji tovrstnih orodij v razvoj in proizvodnjo zdravil ter hkrati odpira zanimiva področja, ki so lahko predmet bodočih raziskav.

Keywords

farmacevtska tehnologija;farmacevtske oblike;filmsko obložene tablete;oblaganje;vrtinčnoslojni oblagalnik;bližnja infrardeča spektroskopija;ramanska spektroskopija;prostorsko filtriranje;multivariatna anliza;

Data

Language:	Slovenian
Year of publishing:	2019
Typology:	2.08 - Doctoral Dissertation
Organization:	UL FFA - Faculty of Pharmacy
Publisher:	[K. Korasa]
UDC:	615.453.5(043.3)
COBISS:	301415424
Views:	215
Downloads:	0
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Other data

Secondary language:	English
Secondary title:	Assessing the applicability of process analytical technology tools in pellet film coating process
Secondary abstract:	The emergence of novel pharmaceutical dosage forms and complex technological processes in the beginning of the 21st century has led to rapid development of systems and technological solutions for enhanced control of medicine manufacturing. A system for designing, analysing, and controlling manufacturing through timely measurements (i.e., during processing) of critical material attributes and critical process parameters with the goal of ensuring final product quality is known as process analytical technology or PAT. Different tools, such as statistical and mathematical data management approaches, process analysers, process control tools, and efficient knowledge management tools are used within the PAT framework. The main focus of our doctoral thesis was to evaluate the applicability of different process analysers in the monitoring and control of the pellet film coating process. Firstly, near-infrared (NIR) spectroscopy, which is the most commonly used real-time analyser for monitoring of pellet coating processes, was investigated. In the second part of the thesis, applicability in determination of crucial pellet attributes of another spectroscopic technique, Raman spectroscopy, was evaluated. In addition, two different approaches for measuring particle size parameters during the coating process were examined, i.e. spatial filtering technique (SFT) and image analysis. Multivariate data analysis was used to achieve high usability of the collected process data. The doctoral thesis consists of four articles published in the recognised scientific journals. In the first part of this thesis a review article is presented. The article overviews different options for monitoring of solid dosage forms coating processes in real-time. NIR spectroscopy is the most frequently evaluated approach in the scientific literature, confirming the wide use of this approach for determination of multiple critical attributes during the film coating process of both tablets and pellets. Raman spectroscopy is also often mentioned in the published literature, but unlike NIR spectroscopy, the applicability in monitoring of pellet coating process is less investigated for this technique. Both spectroscopic techniques are considered as ideal PAT analysers, since multiple solid dosage form attributes, such as coating thickness, coating weight, active ingredient content, and drug release rate can be predicted from the spectral data with the use of multivariate models. Theoretically, Raman spectroscopy is less suitable for the measurement of polar molecules than NIR spectroscopy. Therefore, NIR spectroscopy is used for determination of water content during the coating process more commonly. Curing process of the polymer films is poorly investigated in case of both spectroscopic techniques. Second group of process analysers comprises techniques for direct coating thickness determination (terahertz pulse imaging or TPI) or direct particle size measurement (chord length analysers and particle image analysers). Several publications confirm high applicability of these techniques. In addition, all analysers from this group are commercially available and thus commonly used in the manufacturing of solid dosage forms. Besides well-established PAT analysers listed above, some novel approaches have emerged recently, i.e. optical coherence tomography, acoustic emission, microwave resonance, and laser induced breakdown spectroscopy. These approaches have high potential to become valuable PAT tools in the near future. The first research article investigated applicability of the SFT probe in particle size determination and applicability of the NIR spectroscopy in water content and film coating thickness measurement in real-time. The SFT probe proved as an efficient tool for monitoring of the coating process, which was capable of determining the increase in pellet size growth rate after each increase of the coating dispersion spray rate. In addition, measured particle size correlated very well with the reference methods of sieve analysis and static image analysis. The biggest drawback of this measuring approach was its inability to detect agglomeration phenomenon, since the SFT in-line measurements did not correlate with the actual number of agglomerates. The results of the NIR probe evaluation were also interesting. The NIR spectra collected during the pellet coating process correlated very well with the reference methods of loss on drying (LOD) and Karl Fischer titration. Consequently, calibrated multivariate models enabled water content prediction in the pellets with altered qualitative composition, where a different type of the polymethacrylic polymer was used. In addition, the NIR probe proved as a suitable analyser for measuring coating thickness during the coating process. The model, calibrated outside the spectral bands characteristic for water, enabled efficient prediction of the pellet coating thickness when coating of an independent batch was performed. Moreover, the NIR spectral data correlated very well with the reduction of the coating thickness when attrition of the pellets had occurred. The findings listed above illustrate wide applicability of the tested PAT analysers during the coating process. A study on the applicability of the NIR spectroscopy was extended with the second research article, which evaluated the possibility of monitoring the curing process of the prolonged release coating. Unlike the first research article, in which the NIR spectra were recorded in an in-line mode, the spectra of pellets were recorded in an at-line mode in the second article. It was shown that curing of the coated pellets led to decreased peak intensities of the components located below the prolonged release polymer coating. A possible explanation for such results was that increased inter-diffusion of the polymer chains and coalescence of the polymer particles caused reduced intensities of the observed peaks. The NIR spectral data was calibrated with the drug release profiles – measured in three time points – and the calibrated model was later used for the prediction of the active ingredient release rate of the independent sample cluster to evaluate the applicability of the tested approach. The predicted values correlated well with the actual drug release rate with the exception of samples with high water content (higher than 4.5 %). Direct effect of water on spectral data or indirect effect of water on the structure of the polymer film were identified as most probable causes for reduced predictive power of the model in case of the samples with high water content. Moreover, it was confirmed in this study that an at-line NIR spectroscopy is capable to determine the film coating thickness, which additionally confirmed the findings presented in our first research article. The second research article has a high scientific added value, since such findings of the pellet curing process evaluation are presented in no other published work so far. In the last research article the possibility to calibrate the model for in-line monitoring of water content and film coating thickness in real-time by measuring the NIR spectra of laboratory samples off-line was presented. The efficiency of such approach, which can significantly reduce the effort needed to calibrate a model for in-line monitoring, was confirmed by coating thickness and water content prediction of three independent pilot scale batches. In the second part of this article, extensive study on the applicability of Raman spectroscopy in both in-line and at-line mode was presented. The findings of the at-line process analyser evaluation showed that Raman spectroscopy was a very efficient tool for coating thickness determination and, surprisingly, was also capable to assess water content in the tested pellets quite accurately. On the other hand, in-line Raman spectroscopy was not capable to predict water content in the pellets. However, the in-line analyser proved as an efficient tool for accurate coating thickness prediction and amount of sprayed coating dispersion prediction during the pellet coating process. Models calibrated with the off-line Raman spectra were used for the in-line prediction of critical pellet attributes and the results showed that above presented novel approach of calibrating multivariate models could also be applicable in the case of Raman spectroscopy. Finally, a robustness of a novel image analyser was evaluated by monitoring pellet coating process of three pilot scale batches in real-time. Particle size parameters measured in-line were consistent with the course of the process. In addition, measured coating thickness in real-time was compared with the coating thickness measured off-line using dynamic image analysis and no significant difference was observed between both measuring principles. Extensive evaluation of four different process analysers was carried out in the present doctoral thesis. The findings of the thesis are an important extension of the existing knowledge about the PAT tools applicability and they simultaneously present some new aspects that had not been explored previously in the existing scientific publications. The presented knowledge can thus help enhance and more efficiently implement such tools in the development and manufacturing of the medicines. Moreover, it raises some new perspectives, which could be a subject of future studies.
Secondary keywords:	Pelete;Disertacije;Filmsko oblaganje;Procesna analizna tehnologija;
Type (COBISS):	Dissertation
Thesis comment:	Univ. v Ljubljani, Fak. za farmacijo
Pages:	217 str.
ID:	15595309