Superficial interactions: the importance of surfaces in the crystallization, stabilization and dissolution of amorphous drugs

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http://urn.fi/URN:ISBN:978-951-51-5738-6
Title: Superficial interactions: the importance of surfaces in the crystallization, stabilization and dissolution of amorphous drugs
Author: Novakovic, Dunja
Contributor: University of Helsinki, Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology
Doctoral Programme in Drug Research
Date: 2020-01-10
Belongs to series: Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis - URN:ISSN:2342-3161
URI: http://urn.fi/URN:ISBN:978-951-51-5738-6
http://hdl.handle.net/10138/308494
Thesis level: Doctoral dissertation (article-based)
Abstract: Active pharmaceutical ingredients can assume a diverse spectrum of solid-state forms. These forms differ in properties that are of utmost importance for pharmaceutical performance, such as solubility, dissolution rate and bioavailability. Thus, selection of a suitable solid-state form is highly important, particularly for the growing number of poorly water-soluble drug molecules. The amorphous (i.e. non-crystalline) form offers an often much needed solubility advantage at the price of thermodynamic physical instability and possible recrystallization. As the number of poorly water-soluble molecules in drug development is growing, so is the interest in the amorphous form and strategies for its stabilization. Formation of amorphous polymeric solid dispersions is the most common answer. However, issues with recrystallization, particularly at the surface, still remain, as well as high polymeric loadings. The importance of differentiating between the surface and bulk properties of pharmaceutical materials is becoming increasingly recognized. Processes such as dissolution or chemical reactions with surrounding materials start from surfaces. For drugs in the amorphous form, inevitable recrystallization starts at the surface. This transformed (partly) crystalline surface thus dictates dissolution (or lack thereof), as well as other properties relevant for manufacturing, shelf-life or administration. This is why understanding, monitoring and manipulating superficial phenomena is of such importance. Most established solid-state analytical methods show no or limited surface specificity. Nonlinear imaging (sum frequency generation (SFG) and coherent anti-Stokes Raman scattering (CARS)) are relatively new solid-state and surface specific methods. Moreover, as imaging methods, they can visualize solid-state distribution at the surface. Therefore, this thesis utilized novel nonlinear imaging approaches to better understand surface solid-state behavior. Further, the importance of surfaces in the crystallization, stabilization and dissolution of amorphous drugs was investigated. The first part of the thesis established surface and solid-state specific non-linear imaging methods capable of distinguishing multiple solid state forms. SFG imaging proved to be an excellent tool in detecting low levels of surface crystallization (undetectable with other analytical methods employed), in particular amorphous transformation to a single crystalline solid-state form. Additionally, multimodal nonlinear imaging (SFG and CARS modalities, each with their own benefits) was used for the first time in pharmaceutical samples to simultaneously differentiate up to three different solid-state forms. The second part of the thesis compared surface versus bulk crystallization and investigated surface crystallization (change in the solid-state form) during storage, as one of the key indicators of pharmaceutical performance. Both the cross-sectional SFG imaging of compressed powders, as well as the SEM morphology of continuous particle tablets allowed visualization of the surface-biased crystallization during storage. Further, the addition of different excipients physically mixed with the drug affected the crystallization of the amorphous drug in the bulk, however, their inability to stabilize the crystallization at the surface was demonstrated. In contrast, thin polymer coatings were successful in delaying the onset of surface crystallization at high humidity and elevated temperature during storage. The final part of the thesis investigated the implications of storage-induced surface crystallization and its stabilization with polymer coatings on pharmaceutical performance during dissolution, as a further necessary step in drug development. It was shown that different extents and natures of surface crystallinity affect drug dissolution. Multimodal nonlinear imaging revealed up to five solid-state forms simultaneously present at the surface, and aided the interpretation of the dissolution profiles. The initial dissolution rates of the short-term stored polymer coated samples were equivalent to those of the unaged uncoated samples. In summary, this thesis demonstrated the importance of surface solid-state properties, and their surface-specific analysis, for understanding the pharmaceutical performance of amorphous formulations during storage and dissolution. With further developments in amorphous drug formulations, the interest in surface crystallization and its prevention in the future will likely increase, together with the demand for surface-specific solid-state analysis. Altogether, it can be expected that in the future the understanding and utilization of surface phenomena will evolve from superficial to comprehensive.Nykyisin lääkevalmisteet ovat usein huomattavasti vaikeampia valmistaa kuin ennen. Yksi syy tähän on se, että lähes 95 % uusista lääkeainemolekyyleistä on niukkaliukoisia. Tämä niukkaliukoisuus voi estää lupaavien lääkeainemolekyylien käytön, koska ne eivät huonon liukoisuuden takia pääse vaikuttamaan elimistössä. Yksi lupaava tapa vähentää niukkaliukoisuuden aiheuttamia ongelmia on muokata lääkeaineen fysikaalista muotoa niukkaliukoisesta kiteisestä muodosta vastaavaksi paremmin liukenevaksi amorfiseksi aineeksi. Käytännön esimerkki tästä on hattaran (amorfinen sokeri) valmistus kiteisestä sokerista. Lapset (ja aikuiset) pitävät hattarasta, koska se tuntuu suussa makeammalta kuin tavallinen sokeri. Makeampi suutuntuma johtuu siitä, että hattarasta sokeri liukenee suun nesteisiin huomattavasti nopeammin kuin tavallinen kiteinen sokeri. Sama ilmiö voidaan havaita myös amorfisilla lääkeaineilla verrattuna vastaaviin kiteisiin lääkeaineisiin. Ongelmana näillä amorfisilla aineilla (kuten hattara) kuitenkin on, että ne ovat epästabiileja ja pyrkivät muuttumaan takaisin alkuperäiseen kiteiseen muotoon (kiteinen sokeri): tästä seuraa aineen liukenemisen huononeminen. Tutkimuksellisesti haasteena on näiden kiteisten ja amorfisten muotojen erottaminen toisistaan luotettavasti ja riittävällä herkkyydellä. Tässä väitöskirjassa esitelläänkin luotettava ja yksinkertainen analyysitekniikka, jolla amorfisesta aineesta puristetun tabletin pintaa analysoimalla voidaan määrittää pinnan ominaisuudet. Tämä pelkän pinnan analysointi on puhtaasta amorfisesta aineesta tehdyille tableteille riittävä, sillä aineen kiteytyminen alkaa juuri tabletin pinnalta. Miten pinnan analysointi sitten tapahtuu? Tämä väitöskirja esittelee pinnan analyysitekniikan, joka on kuin suoraan tieteiselokuvista: lääkeainepintojen analysointiin käytetään mikroskooppia, missä laserilla saadaan aikaan erilaisia värisävyjä riippuen aineen fysikaalisesta tilasta. Väitöskirja on siis keskittynyt amorfisten lääkeainepintojen stabilointiin ja pinnan analysointiin stabiiliuden määrittämiseksi. Väitöskirjassa saatiin vahvistettua se, että amorfisen aineen (kuten hattarapuriste) stabiiliuden kannalta pinta on kaikista tärkein kohta. Pinnan ominaisuuksien tarkka analysointi tässä työssä käytetyn uuden tekniikan avulla auttaa ymmärtämään amorfisista lääkeaineista valmistettujen tablettien stabiilius ominaisuuksia.
Subject: Pharmaceutical technology
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