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Mutual impact of phase separation/crystallization and water sorption in amorphous solid dispersions. Christian Luebbert, Maximilian Wessner, and Gabri...
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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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Molecular Pharmaceutics

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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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Molecular Pharmaceutics

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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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