Mechanistic Studies of Drug Dissolution Testing : Implications of solid phase properties and in vivo prognostic media

Abstract

Drug absorption after oral administration requires that the drug first dissolves into gastro-intestinal tract liquids. In vivo dissolution of a drug is affected by physiological and drug-related physicochemical factors. In the case of poorly water-soluble drugs, in vitro dissolution testing at various stages of drug development is especially important, since the absorption is predominantly limited by the dissolution rate. Varying dissolution rates, possible for different physical structures of the same chemical entity (known as polymorphs), for example, can lead to varying degrees of bioavailability and, potentially, result in therapeutic failure. Traditionally, pharmaceutical dissolution testing has relied on determination of the dissolved drug concentration from liquid phase. This has led to poor understanding (and possible underestimation) of the connection between the change in solid phase and dissolution behaviour. Thus, new powerful approaches are needed. To correlate in vitro dissolution results of drug products with in vivo behaviour often requires the use of dissolution methods reflecting conditions in the gastro-intestinal tract. For such purpose, various physiologically based dissolution media have been proposed.

In this thesis, solid phase analysis was combined with dissolution determinations to provide in depth understanding of the effects of solid state properties on the intrinsic dissolution rate of active pharmaceutical ingredients (API). A new approach to dissolution testing, which involved simultaneous in situ solid phase analyses of the dissolving sample and measurement of dissolved concentrations in the dissolution medium, were utilized to explain the implications of solvent-mediated solid phase conversions on dissolution processes. Simplified dissolution media were developed and studied for the prediction of in vivo behaviour of Biopharmaceutics Classification System (BCS) class II drugs.

Quantitative solid phase analysis using Raman spectroscopy was successfully performed in situ during the intrinsic dissolution testing of APIs. Direct solid phase analysis in tandem with measurement of dissolved concentrations enabled molecular level insight into changes in dissolution rate due to hydrate formation. Against expectations, preferred orientation of drug crystals during sample preparation was shown to have only minor effects on dissolution results during intrinsic dissolution. Importance of dissolution medium on solvent-mediated conversion kinetics was revealed as bile salts were shown to be able to interact with the dissolving solid by hydrogen bonding mechanisms. To predict in vivo behaviour of BCS class II drugs, simple and cost-effective conventional surfactant media were shown to be potential substitutes for more complex, physiologically based Fasted State Simulated Intestinal Fluid (FaSSIF).

This thesis provides directly applicable new tools for the dissolution experiments in pharmaceutical drug development. In-depth information of solid state properties on dissolution rate assists in drug candidate selection as well as in explaining and controlling the behaviour of APIs in the final drug products. The use of simplified, in vivo prognostic dissolution media has potential of saving development time and costs for formulation development and regulatory purposes.

Suun kautta annostellun lääkkeen imeytymisen edellytyksenä on liukeneminen ruuansulatuskanavan nesteisiin. Lääkkeen liukenemiseen in vivo vaikuttavat useat fysiologiset ja fysikokemialliset tekijät. Etenkin niukkaliukoisten lääkeaineiden testaaminen liukenemiskokein in vitro on tärkeää, koska muutokset mm. lääkeaineen fysikaalisissa ominaisuuksissa voivat heijastua liukenemiskäyttäytymiseen ja vaarantaa lääkkeen terapeuttisen käytettävyyden.

Väitöskirjatyössä selvitettiin lääkeaineiden kiinteän tilan ominaisuuksien vaikutuksia ominaisliukenemisnopeuteen käyttämällä uudenlaista lähestymistapaa; kiinteän tilan muutoksia seurattiin Raman spektroskopian avulla yhtäaikaisesti (in situ) liuenneen aineen konsentraation määritysten kanssa. Saavutettu molekyylitason tietämys lääkeaineen kiinteän tilan ominaisuuksien vaikutuksesta liukenemiskäyttäytymiseen soveltuu apuvälineeksi uusien lääkekandidaattien valinnassa sekä auttaa selittämään ja kontrolloimaan lääkeaineiden käyttäytymistä lääkevalmisteessa.

Usein in vitro liukenemiskoetulosten käyttäminen kuvaamaan in vivo elimistössä tapahtuvaa liukenemista edellyttää fysiologisten olosuhteiden simulointia. Väitöskirjatyössä tutkituttujen yksinkertaistettujen, in vivo liukenemista ennustavien väliaineiden käyttö voi auttaa lyhentämään lääkevalmisteiden kehitysaikaa ja säästämään kehityskustannuksissa.