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Mutual impact of phase separation/crystallization and water sorption in amorphous solid dispersions Christian Luebbert, Maximilian Wessner, and Gabriele Sadowski Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b01076 • Publication Date (Web): 08 Jan 2018 Downloaded from http://pubs.acs.org on January 10, 2018
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Molecular Pharmaceutics
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Mutual impact of phase separation/crystallization
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and water sorption in amorphous solid dispersions
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Christian Luebbert, Maximilian Wessner, Gabriele Sadowski*
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*Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, TU
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Dortmund University, Emil-Figge-Str. 70, D-44227 Dortmund, Germany.
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GRAPHICAL ABSTRACT:
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ABSTRACT: The molecular integration of poorly-water-soluble active pharmaceutical
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ingredients (APIs) in a suitable polymeric matrix is a possible approach to enhance the
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dissolution behavior and solubility of these APIs. Like all newly-developed pharmaceutical
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formulations, these formulations (often denoted as amorphous solid dispersions (ASDs)) need to ACS Paragon Plus Environment
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undergo storage stability tests at defined relative humidity (RH) and temperature conditions. In a
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previous work (Int. J. Pharm. 532 (2017) 635-646), it was shown that thermodynamic modeling
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can be successfully used to predict the long-term stability of ASDs against API crystallization
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and moisture-induced amorphous-amorphous phase separation (MIAPS). This works in turn
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demonstrates the prediction of water sorption in ASDs accounting for potentially occurring API-
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crystallization and MIAPS. The water sorption and phase behavior of ASDs containing the APIs
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felodipine and ibuprofen incorporated in three different hydrophilic polymers poly(vinyl
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pyrrolidone), poly(vinyl acetate), and poly(vinyl pyrrolidone-co-vinyl acetate) at the conditions
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25 °C/60% RH and 40 °C/75% RH was predicted using the Perturbed-Chain Statistical
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Associating Fluid Theory (PC-SAFT). The predictions were successfully validated via two-years-
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lasting water-sorption experiments. It was shown that crystallization of the API and MIAPS on
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the one hand and water sorption in the ASDs on the other hand dramatically influence each other
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and that this behavior can even be quantitatively predicted by PC-SAFT which provides valuable
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insights already at early stages of formulation development.
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KEYWORDS: amorphous solid dispersion, water sorption, moisture-induced amorphous-
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amorphous phase separation, long-term stability, PC-SAFT.
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1 INTRODUCTION
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Poorly water-soluble active pharmaceutical ingredients (APIs) are challenging for
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pharmaceutical development as sufficient bioavailability and dissolution characteristics can only
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be achieved by a suitable formulation strategy, e.g. via dissolving the API amorphously in a
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suitable polymer (so-called amorphous solid dispersion (ASD)). An appropriate polymer
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stabilizes the amorphous state of the API throughout the shelf-life of the formulation (if the ACS Paragon Plus Environment
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Molecular Pharmaceutics
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solubility of the crystalline API in the polymeric matrix is sufficiently high) and enhances the
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dissolution performance in the gastrointestinal tract (e.g. by choosing a hydrophilic polymer).
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Using those pharmaceutical formulations requires long-term stability tests according to the
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International Conference on Harmonization (ICH) Guideline Q1A(R2)1, which defines storage
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temperatures and storage relative humidities (RH). Common storage conditions are 25 °C/60%
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RH (storage condition for standard long-term stability tests) or 40 °C/75% RH (storage condition
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for accelerated long-term stability tests). As shown in previous works2–4, RH has a huge impact
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on the stability of ASD formulations against API crystallization5, moisture-induced amorphous-
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amorphous phase separation (MIAPS) crystallization and also affects the glass-transition
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temperature6 of the API/polymer mixture3. The water content in ASDs can be determined
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gravimetrically (e.g. by dynamic vapor sorption measurements7,8, thermogravimetric analysis, or
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storage in the presence of a saturated salt solution9), via NMR-, Raman- or IR-spectroscopy10, or
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via Karl-Fischer-Titration.
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Andronis et al. showed that already a few mass percent of water uptake in amorphous
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Indomethacin (IND) accelerated the crystallization velocity by several orders of magnitude11.
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Konno and Taylor found that the nucleation rate of pure amorphous Felodipine (FEL) increased
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by factor 20 after the uptake of only 1 wt% water7. Moreover, MIAPS was qualitatively2,12–16
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observed and recently also quantitatively17 investigated for several API/polymer formulations.
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Additive approaches (weighted sum of water sorption of the individual components)8,18,19 do
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not provide correct measures of the water sorption20 in ASD formulations as they do not at all
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account for the interactions between all formulation components API, polymer, and water.
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Instead it is important to note, that the molecular state of an ASD, i.e. whether it is (I)
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homogeneous and amorphous, or (II) demixed into two amorphous phases, or (III) contains API
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crystals strongly depends on the amount of absorbed water and vice versa. Thus, phase behavior
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of ASDs and their water sorption are inextricably linked and can only be understood when
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considered simultaneously2–4.
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So far, no systematic work has been published modeling the water sorption in ASDs
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considering the physical state of the ASD (amorphous, MIAPS and/or API crystallization) along
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with long-term sorption experiments. Therefore, in this work we predicted the water content in
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ASD formulations using the Perturbed-Chain Statistical Associating Fluid Theory21 (PC-SAFT)
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and explicitly considering the physical state of the ASDs. PC-SAFT has been already
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successfully used to model the phase behavior of ASDs22–25, the aqueous solubility of
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crystalline26 and amorphous27 APIs, the dissolution of APIs in aqueous media28 and the influence
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of RH on the API/polymer phase behavior2,3.
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The water-sorption predictions in this work were verified by two-years enduring long-term
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sorption measurements. Poly (vinyl pyrrolidone) (PVP) and poly(vinyl acetate) (PVAC) were
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selected as representatives for very hydrophilic and hydrophobic polymeric excipients,
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respectively. The copolymer poly(vinyl pyrrolidone-co-vinylacetate) (PVPVA) was selected as
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example for slightly hydrophilic excipients.
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2 WATER SORPTION IN ASDs
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In order to correctly describe the water sorption in ASDs, all possible phase transitions
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(MIAPS and crystallization) must be considered as they certainly influence the water sorption.
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ASD schematic phase diagrams along with the resulting water-sorption profiles at different
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temperatures are shown in Fig 1.
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Fig. 1. Schematic phase behavior and water-sorption profiles of an API/polymer formulation at constant RH and varying temperatures (Figures a, b, and c). Upper figures: Temperature-dependent solubility and MIAPS in the API/polymer/water system as function of the API mass fraction in the water-free formulation ( ). The solubility line is black; the MIAPS region is marked in gray. Lower figures: amount of water absorbed in the ASD at indicated temperature as function of . Solid lines: water sorption of homogeneous formulations; dashed-dotted lines: water sorption of formulations undergoing MIAPS; dotted lines: water sorption after crystallization. Thermodynamically-metastable states are thin lines, whereas thermodynamically-stable states are thick lines. Thin vertical lines connect identical states in upper and lower figures.
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The upper part in Fig. 1 depicts the solubility temperature and the MIAPS region of an
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API/polymer ASD as function of the API mass fraction in the water-free formulation ( ).
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Such diagrams show the equilibrium solubility line (formulations stored below this line will
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eventually crystallize) and the MIAPS region (formulations stored within this region will
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eventually undergo MIAPS) as described in detail in earlier works2–4. These diagrams do account
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for the water sorption in the formulation at constant RH and are therefore the phase diagrams of
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the water-containing formulations (although for practical reasons, is shown on the x-axis).
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The water sorption depends on the amount of the (hydrophobic) API in the (more or less
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hydrophilic) polymer as well as on the physical state of the formulations. This is shown in the
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three lower diagrams of Fig. 1. Herein, the total mass fraction of water absorbed in the ACS Paragon Plus Environment
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formulations ( ) is depicted for three different storage temperatures Ta, Tb and Tc (depicted
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in the upper diagrams) of the same API/polymer system and as function of .
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Fig. 1a illustrates the phase behavior and the corresponding sorption behavior at constant RH
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and a storage temperature Ta which lies above both, the MIAPS region and the solubility line.
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Thus, neither crystallization nor MIAPS is expected to occur. The schematic corresponding water
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sorption profile shown in the lower diagram of Fig. 1a is characterized by a steady decrease of
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the amount of absorbed water from a high value in the API-free hydrophilic polymer on the left-
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hand side of the diagram to a very low value in the pure, hydrophobic API on the very right side
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of the diagram.
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At storage temperature Tb (Fig. 1b), crystallization and MIAPS may occur depending on the
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API content in the formulation . In regions II and IV, the formulations stored at Tb are
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located above solubility line and MIAPS region (Fig. 1b) and thus will remain amorphous at the
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given RH. The water sorption in these regions will therefore follow the same line as in Fig. 1a.
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However, formulations with API contents in the regions III and V will not remain amorphous, but
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undergo a phase transition upon storage.
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As long as no phase transition occurs, the water content in the (thus metastable) formulations
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will correspond to that of the thin solid line in the lower Fig. 1b. Upon formation of crystalline
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API (region V), the overall water content decreases compared to the amorphous state as crystals
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do not incorporate water in the crystal lattice. The formulation will therefore absorb less water
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(dotted line in lower Fig. 1b) than in the fully amorphous state. Similarly, during MIAPS (region
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III) two amorphous (liquid) phases (API-rich and API-poor) evolve and these phases absorb
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different amounts of water as they differ in hydrophilicity. The final water content in those
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demixed formulations will again be different form the one of the homogeneous ASD and will
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correspond to that of the dash-dotted line in the lower Fig. 1b. ACS Paragon Plus Environment
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At storage temperature Tc, the solubility line now lies far on the left side of the diagram (upper
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Fig. 1c). This means, that the formulations remain amorphous only for the very low API
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concentrations in region VI. At least after infinite time (in equilibrium), API crystallization is
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expected to occur in regions VII, VIII, IX and MIAPS will occur in region VIII. As long as the
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formulations remain homogeneous and amorphous (i.e. before reaching the equilibrium state),
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water will be absorbed according to the same line as in lower Fig. 1a (thin solid line in lower Fig.
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1c). Formulations undergoing MIAPS will absorb water according to the gray dash-dotted line
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lower Fig. 1c. Hence, as MIAPS is metastable at this temperature, crystallization is
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superimposing MIAPS and is thus the thermodynamically-stable state (regions VII-IX). After
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reaching the equilibrium state, these formulations will show API crystals in equilibrium with an
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amorphous phase which has a composition according to the intersection between regions VI and
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VII. This means, the API is almost completely depleted from the amorphous phase which in turn
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becomes much more hydrophilic than the original formulation. Thus, for this specific case, API
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crystallization enhances the water content in the formulation according to the dotted line in the
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lower Fig. 1c.
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It becomes obvious that the water sorption may extremely vary depending on the physical state
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of the formulation. API crystallization might decrease (Fig. 1b, region V) or increase (Fig. 1c,
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regions VII-IX) the water content in formulations, depending on the hydrophilicities of the
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involved API and polymer and the solubility of the API in the polymer/water mixture at the
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considered storage condition.
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2.1 THERMODYNAMIC MODELING
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To predict the sorption behavior described in the previous section, the thermodynamic
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equilibrium of the water vapor (V), the amorphous formulation (L) and the crystallized API
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(solid, S) needs to be considered. The water sorption in homogenous amorphous formulations
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(Fig. 1, regions I, II, IV, VI) can be calculated by considering the equilibrium of V and L, only.
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At thermodynamic equilibrium, for each component i the chemical potential µ needs to be the
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same in the two phases. Assuming that API and polymer cannot evaporate and water is the only
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component present in both phases V and L leads to the following equilibrium condition: =
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(1)
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Whereas it can be assumed that the chemical potential of water in the vapor phase is not
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influenced by the presence of air, the chemical potential of water in the amorphous phase does
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depend on the presence and amount of both, the API and the polymer. Thus, the vapor-liquid
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equilibrium condition given in Eq. 1 results in Eq. 2 =
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=
(2)
where the relative humidity RH is defined as the ratio of the water partial pressure .
in the
In Eq. 2, and are the
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vapor phase and the vapor pressure of pure water
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water mole fraction and the water activity coefficient in the amorphous formulation, respectively.
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accounts for the intermolecular interactions among API, polymer, and water and is
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obtained in this work from the Perturbed-Chain Statistical Associating Fluid Theory (PC-
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SAFT)21,29,30.
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Crystallizing API (regions V, VII-IX) needs to be considered by additionally taking into
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account the equilibrium of the API between the solid phase S and the amorphous phase L leading
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to Eq. 3:
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! =
(3)
Assuming that the solid phase S consists of pure crystalline API which is in equilibrium with an amorphous phase L containing all three components polymer, water and API leads to Eq.431:
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Molecular Pharmaceutics
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