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Impact of Polymer Type and Relative Humidity on the LongTerm Physical Stability of Amorphous Solid Dispersions Kristin Lehmkemper, Samuel O. Kyeremateng, Oliver Heinzerling, Matthias Degenhardt, and Gabriele Sadowski Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00492 • Publication Date (Web): 19 Oct 2017 Downloaded from http://pubs.acs.org on October 21, 2017

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Molecular Pharmaceutics

Impact of Polymer Type and Relative Humidity on the Long-Term Physical Stability of Amorphous Solid Dispersions Kristin Lehmkemper1,2, Samuel O. Kyeremateng1,*, Oliver Heinzerling1, Matthias Degenhardt1 and Gabriele Sadowski2,** 1

AbbVie Deutschland GmbH & Co. KG, Global Pharmaceutical R&D, Knollstraße, D-67061 Ludwigshafen am Rhein, Germany 2

TU Dortmund, Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, Emil-Figge-Str. 70, D-44227 Dortmund, Germany

KEYWORDS. amorphous solid dispersion, polymer, thermodynamic model, phase behavior, physical stability, excipient

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ABSTRACT The purpose of this work is to compare the long-term physical stability of amorphous solid dispersion (ASD) formulations based on three different commercially-used excipients, namely,

poly(vinylpyrrolidone)

K25

(PVP),

poly(vinylpyrrolidone-co-vinyl acetate)

(PVPVA64), and hydroxypropyl methylcellulose acetate succinate 126G (HPMCAS), at standardized ICH storage conditions, 25 °C/0% relative humidity (RH), 25 °C/60% RH, and 40 °C/75% RH. Acetaminophen (APAP) and naproxen (NAP) were used as active pharmaceutical ingredients (APIs). 18-months long stability studies of these formulations were analyzed and compared with the API/polymer phase diagrams, which were modeled and predicted by applying the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon-Taylor or Kwei equation. The study showed that at dry storage, the solubility of the APIs in the polymers as well as the kinetic stabilizing ability of the polymers increase in the following order: HPMCAS < PVPVA64 < PVP. RH significantly reduces the kinetic stabilization as well as NAP solubility in the polymers, while the impact on APAP solubility is small. The impact of RH on the stability increases with increasing hydrophilicity of the pure polymers (HPMCAS < PVPVA64 < PVP). The experimental stability results were in very good agreement with predictions confirming that PC-SAFT and Kwei equation are suitable predictive tools for determining appropriate ASD compositions and storage conditions to ensure long-term physical stability.


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INTRODUCTION The preparation of amorphous solid dispersions (ASDs) is an established formulation technique for improving the bioavailability of poorly water-soluble active pharmaceutical ingredients (API) by increasing solubility, wettability and dissolution rate.1-3 An amorphous API usually shows a higher solubility than its crystalline form.4,5 By generating ASDs, an amorphous API is embedded in an amorphous excipient to prevent it from crystallization. Especially water-soluble, amorphous polymers have successfully been used as ASD excipients.1-3,6 In literature, several polymers have been investigated for pharmaceutical applications.6-8 Synthetic poly(vinylpyrrolidone) (PVP)-based polymers are one main ASD-excipient group913

, comprising homopolymers of only vinyl-pyrrolidone monomers as well as copolymers like

poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). When used as ASD excipients, PVP and PVPVA increase the API dissolution rate in aqueous media compared to the pure crystalline API.13,14 In addition, PVP and PVPVA show solubilizing properties by forming water-soluble complexes with the APIs7,15, which increases the API solubility15 and therefore reduces the driving force for API recrystallization after dissolution. Semi-synthetic modified celluloses, like hydroxypropyl methylcellulose acetate succinate (HPMCAS), are another important ASD-excipient group showing similar properties in terms of enhancing API dissolution.16,17 In some cases, HPMCAS-ASD formulations release the embedded API in excess of their crystalline solubility and this enhanced concentration is maintained for a long time, up to several days8,17, as HPMCAS forms amorphous API/polymer nanostructures.17 Generally, compared to PVP and PVPVA, HPMCAS shows an higher ability of stabilizing supersaturated aqueous API solutions.8,18-20 For maintaining the bioavailability advantages of the amorphous API in an ASD, the physical long-term stability is an important criterion in the development of oral solid dosage forms. ASDs are considered to be physically stable as long as no liquid-liquid phase 3 ACS Paragon Plus Environment


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separation or rather recrystallization of the API occurs. From thermodynamic perspective, the amorphous polymer serves as a solvent for the API so that the ASD is thermodynamically stable as long as the API content is below its solubility in the polymer.21 Below their glasstransition temperature, the polymers as well as the ASD formulations also show very low molecular mobility, so that recrystallization is inhibited kinetically even if the API load is higher than its solubility in the polymer. Consequently, thermodynamically-unstable amorphous formulations can be kinetically stabilized to the extent that they do not recrystallize during their shelf-life.9,22 Thus, the solubilizing and kinetic stabilizing abilities of the polymer mainly determine the long-term physical stability of the ASD formulation. For this reason, physical stability of ASD varies depending on the choice of the polymeric excipient. Moreover, relative humidity (RH) has a strong impact on the physical stability of ASD formulations.23-25 Different polymeric excipients show different hydrophilicities: PVP, which is a homopolymer of hydrophilic vinylpyrrolidone monomer, is a highly hygroscopic substance and absorbs around 28 wt % of water at room temperature (25 °C) and 75% RH.25 PVPVA64 -the most commonly used PVPVA form- contains 40 wt % hydrophobic vinyl acetate monomer besides the hydrophilic vinylpyrrolidone monomer and therefore absorbs less water than PVP (19 wt % at 25 °C/75% RH25). Modified celluloses are less hygroscopic than PVP and PVPVA64, i.e. pure HPMCAS 126G (DOW, Bomlitz, Germany) absorbs only 6 wt % water at 25 °C/75% RH. Because of this difference in the water-sorption properties of the different polymer types, RH is expected to have an excipient-related effect on the physical stability of ASDs. In this work the physical stability of ASD formulations with three different commerciallyused excipients, PVP K25, PVPVA64, and HPMCAS 126G, was investigated. Naproxen ((S)(+)-2-(6-Methoxy-2-naphthyl)propionic acid, NAP) and acetaminophen (N-Acetyl-p-


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aminophenol, APAP) were used as model APIs. The chemical structures of the used substances are shown in Figure 1. (a)

(d)

(b)

(e)

(c)

Figure 1. Chemical structures of (a) PVP, (b) PVPVA (n/m = 6/4 (wt/wt) for PVPVA64), (c) HPMCAS, (d) NAP and (e) APAP. Stability studies of ASDs with the three different polymeric excipients were conducted for 18 months at dry storage (25 °C/0% RH) and at standardized conditions, 25 °C/60% RH and 40 °C/75% RH, which were purposed by International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) for long-term and accelerated studies, respectively. Stability studies for such a long storage time can rarely be found in literature. Before performing these long-term stability studies, the physical stability at the dry and ICH conditions was modeled and predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT)26 and the Kwei equation27 for calculating the solubility of the APIs in the polymers and the glass-transition temperature of the amorphous formulations, respectively. 5 ACS Paragon Plus Environment


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PC-SAFT has already been successfully applied for modeling several types of phase equilibria, such as API solubilities in API/solvent28,29 or API/polymer11,21 systems (solidliquid equilibria, SLE) as well as solvent-vapor sorption in polymer systems30,31 (vapor-liquid equilibria, VLE). In recent works, the influence of RH on the API/polymer systems was successfully predicted by simultaneously solving SLE and VLE equations using PCSAFT.25,32 It was also shown that PC-SAFT is a promising alternative for the Flory-Huggins model32. The Flory-Huggins model has successfully been used for calculating API solubility in polymers33-35, but in some cases, also showed poor fits for certain systems (e.g. mannitol/PVP36 and Tadalfil/PVPVA6437). The glass-transition temperature of amorphous pharmaceuticals is most commonly predicted based on densities and glass-transition temperatures of the pure components using the Gordon-Taylor equation.38-40 But strong specific interactions might lead to a deviation of the glass-transition temperature from Gordon-Taylor prediction.27,40-43 The Kwei equation extends the Gordon-Taylor equation by introducing a binary parameter q, which accounts for the specific interaction between the molecules, e.g. hydrogen bonding. The modeled-based comparison of the physical stability of ASDs with different polymeric excipients reduces experimental effort and time resource during ASD development as it enables screening for a suitable polymeric excipient and an applicable API load using only very few experimental data.

MODELING

Relation between physical stability of ASDs and the API/polymer phase diagram The solubility temperature and the glass-transition temperature, which mainly determine the thermodynamic and the kinetic stability of an ASD formulation, respectively, can be visualized in a phase diagram, as shown in Figure 2.21,32


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Figure 2. Schematical phase diagram of an API/polymer-ASD formulation. The full curve represents the solubility of the crystalline API in the polymer and the dashed curve the glasstransition temperature of the amorphous formulation. The curves divide the phase diagram into four areas: (I) thermodynamically-stable melt, (II) thermodynamically-stable glass, (III) kinetically-stable glass and (IV) thermodynamically- and kinetically-unstable melt. Figure 2 shows that solubility line and glass-transition temperature line divide the phase diagram into four areas. The solubility line marks the maximum API content which can be dissolved in the polymer at a certain temperature. The amorphous formulation is thermodynamically stable as long as the API content is lower than its solubility in the polymer, which corresponds to the areas I and II located left of the solubility line. Thus, all ASD formulations located either on or left of the solubility line will remain amorphous for infinite storage time. When the API content exceeds its solubility in the polymer -right of the solubility line (areas III and IV)- recrystallization of the API is the thermodynamically most-stable case. Consequently, the API in all ASD formulations right of the solubility line will eventually crystallize resulting in a residual amorphous API/polymer phase, in which the API content equals the API solubility in the polymer at that temperature. For a supersaturated ASD formulation (right of the solubility line) stored at a certain temperature, the distance between the solubility line and the API content correlates to the thermodynamic driving force for API crystallization.44 The glass-transition-temperature line separates melt formulations above the line (areas I and IV) from glassy formulations below the line (in the areas II and III). In the glassy state the 7 ACS Paragon Plus Environment


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molecular mobility is low, which leads to kinetic stabilization of supersaturated ASD formulations in area III. Kinetic stabilization increases with increasing distance between storage temperature and the glass-transition temperature of the ASD.22 All things considered, ASD formulations to the left of the solubility line are thermodynamically stable and thus never recrystallize. To the right of the solubility line, ASD formulations furthest from the solubility line and those located above or closely below the glass-transition temperature are expected to be least physically stable, and thus to recrystallize first. Solubility temperatures of APIs in polymers and the glass-transition temperatures of ASDs are usually determined by differential scanning calorimetry (DSC)45,46 and only accessible for dry systems. Even for dry systems, the solubility temperatures of APIs in polymers are also only accessible via DSC measurements at high API contents resulting in temperatures significantly higher than the glass transition of the ASD. Therefore, in this work thermodynamic modeling is used for extrapolating the DSC data to common storage temperatures and relative humidities as successfully conducted in previous works25,32.

Calculation of the API solubility in the polymer at dry and humid conditions In an ASD formulation, the API (solute) is dissolved in the amorphous polymer (solvent). The solubility line is calculated from a solid-liquid-equilibrium (SLE), where the solid phase (S) of pure crystalline API is in equilibrium with the amorphous (=liquid) API/polymer-phase (L). In thermodynamic equilibrium, the chemical potential of the API is the same in the two phases which results in the solubility equation Eq 1.47

x

L API

=

1 γ LAPI

SL SL SL  ∆h SL   T  ∆c p,0,API   T0,API  T0,API 0,API   exp− 1 − − ln − + 1  RT  T0SL,API  R   T  T  


(1)

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x LAPI is the solubility of the API, given as maximum mole fraction of API, which can be dissolved in the liquid phase. R is the universal gas constant (8.314 J mol-1 K-1) and T is the SL SL temperature in Kelvin. T0SL ,API , ∆h 0 , API and ∆cp,0,API are melting temperature, enthalpy of fusion

and difference between solid and liquid heat capacity of the API, respectively. The melting L properties of NAP and APAP are summarized in Table 1. The activity coefficient γ API of the

API in the liquid phase is calculated from PC-SAFT as described below.

Table 1. Melting properties of NAP and APAP API

T0SL ,API

∆hSL 0,API

∆cSL p,0,API

(K) (kJ/mol) (J/(mol·K)) NAP 429.47 31.5 87.44 APAP 443.60 27.1 99.80

Ref. 29 48

ASD formulations stored at humid conditions may absorb water which influences the solubility line. Therefore, a vapor-liquid-equilibrium for water (VLE) has to be considered in addition to the SLE of the API.25,32 The vapor phase (V) is assumed to contain water vapor and air only, while the liquid phase (L) consists of the amorphous API, the polymer and water. The solid phase (S) is considered as the pure crystalline API. In thermodynamic equilibrium, the chemical potential of water in the liquid phase equals the chemical potential of water in the vapor phase. The relative humidity (RH) is defined as the ratio of the partial pressure of water in the vapor phase p Vwater and the vapor pressure of pure water p LV water at the same temperature. According to the VLE condition, it can be obtained from the mole fraction of absorbed water x Lwater in the ASD using Eq 2. RH =

p Vwater × 100 % = γ Lwater x Lwater × 100 % p LV water

(2)

γ Lwater is the activity coefficient of water in the liquid phase which considers deviations from

the ideal solution and accounts for the presence of API and polymer in the liquid phase. Eqs 1 9 ACS Paragon Plus Environment


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and 2 were solved simultaneously for predicting the amount of absorbed water and the solubility of the APIs in the polymer-water mixture exposed to a certain RH. The liquid-phase L activity coefficients γ API and γ Lwater of the API and water, respectively, were calculated with

PC-SAFT, which is introduced in the next section. For presenting the solubility line in the temperature/API-content diagram as presented in L Figure 2, the solubility mole fraction x API in the water-containing formulation is converted

into the API content in wt % in the water-free ASD using Eq 3. API content =

x LAPI M API × 100 wt % x LAPI M API + x Lpolymer M polymer

(3)

x Lpolymer is the mole fraction of the polymer in the water-containing liquid phase. MAPI and

Mpolymer are the molar masses of API and polymer, respectively.

PC-SAFT PC-SAFT (Perturbed-Chain Statistical Associating Fluid Theory) is an equation of state, where the residual Helmholtz energy ares is calculated according to Eq 4 from the sum of a hard-chain reference term ahc and perturbation terms adisp and aassoc, for van der Waals attraction forces (dispersion) and hydrogen bonds (association), respectively. ares is then used L for calculating the activity coefficients γi of component i in a liquid mixture. The required

equations were presented in detail in former works.26,28

a res = a hc + a disp + a assoc

(4)

For calculating the Helmholtz-energy contributions in Eq 4, five PC-SAFT pure-component parameters for each associating component are required: each component molecule is seg considered as a chain of m i spherical segments with the segment diameter σi. The

Helmholtz-energy contribution due to the dispersion adisp between segments of different 10 ACS Paragon Plus Environment

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molecules is calculated using the dispersion-energy parameter u i k B , where k B is the Boltzmann constant. The association contribution aassoc depends on the associationenergy parameter

ε AiBi k B

and the association-volume parameter

κAiBi

. The number of

assoc association sites N i (electron acceptors and electron donators) that can form hydrogen

bonds is determined from the molecular structure of the component. Detailed expressions for the Helmholtz-energy contributions in Eq 4 can be found in former works.26,49 Purecomponent parameters of all substances used in this work are summarized in Table 2.

Table 2. PC-SAFT pure-component parameters of NAP, APAP, PVP K25, PVPVA64, HPMCAS 126G and water used in this work component i

Mi

mseg i Mi

σi

ui kB

ε AiBi kB

κAiBi

N assoc i

Ref.

 g   mol  (-)  (Å) (K) (K) (-)     mol   g  11 NAP 230.26 0.0352 2.939 229.450 934.2 0.02 2/2 28 APAP 151.16 0.0498 3.508 398.284 1994.2 0.01 2/2 25 PVP 25700 0.0407 2.710 205.599 0 0.02 231/231 32 PVPVA64 65000 0.0372 2.947 205.271 0 0.02 653/653 HPMCAS 150000 0.0489 2.889 298.047 1602.3 0.02 931/931 this work* 50 water 18.02 0.0669 2.793 353.945 2425.7 0.0451 1/1 *Fitted to temperature- and concentration dependent densities of HPMCAS solutions in ethyl acetate and the RH-dependent sorption of water by HPMCAS. The corresponding results for measurement and modeling are given in the Supporting Information.

In some cases the dispersion-energy parameter uij in a binary mixture of the components i and j, which is determined from the geometric mean of the pure-component dispersion-energy parameters ui and uj, has to be corrected by a binary interaction parameter kij according to Eq 5. In this work kij is either a constant or linearly depending on the temperature (Eq 6).

u ij = (1 − k ij ) u i u j

(5)

k ij = k ij,m ⋅ T ( K ) + k ij,b

(6)



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kij,m and kij,b represent the slope and the intercept, respectively, of kij as function of the temperature in Kelvin. The binary interaction parameters used in this work are summarized in Table 3.

Table 3. Binary PC-SAFT interaction parameters kij used in this work component i NAP

component j kij,m kij,b Ref. PVP 0 -0.0782 32 PVPVA64 0 -0.0574 32 HPMCAS 0 -0.0289 this work* water 0.000227 -0.0612 29 APAP PVP 0 -0.0412 32 PVPVA64 0 -0.0563 32 HPMCAS 0 0.0196 this work* water 0.000177 -0.0505 51 water PVP 0 -0.1480 25 PVPVA64 0 -0.1560 32 -0.0358 this work** HPMCAS 0 *Fitted to API solubility in HPMCAS measured using DSC. The corresponding measurement and modeling results are given in the Results section. **Fitted to RH-dependent sorption of water in HPMCAS. The corresponding results for measurement and modeling are given in the Supporting Information.

Calculation of the glass-transition temperature of ASDs The most common equation for calculating the glass-transition temperature Tg of ASDs is the Gordon-Taylor equation38,40,43, which is shown in Eq 7.

∑K w T ∑K w i

Tg =

i

g ,i

(7)

i

i

i

i

wi and Tg,i are the amount in wt % of the components i (API, polymer, and water) and the glass-transition temperatures in Kelvin, respectively. Ki is calculated from pure-component densities ρi and pure-component glass-transition temperatures Tg,i using Eq 8, where component i is API, polymer, or water.

Ki =

ρAPITg,API

(8)

ρiTg,i


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The Gordon-Taylor equation was used for predicting glass-transition temperatures of the PVP- and PVPVA64-ASD formulations at dry and humid conditions. The experimentally-determined glass-transition temperatures of the water-free HPMCASASD formulations strongly deviated from Gordon-Taylor prediction. For this reason, the Kwei equation27, an extension of the Gordon-Taylor equation, was used for these systems. The Kwei equation considers specific interactions (e.g. hydrogen bonding) between API and polymer by using the binary parameter qAPI,polymer (Eq 9). Specific interactions between either the API or the polymer and water were neglected (qAPI,water = 0 and qpolymer,water = 0).

∑K w T ∑K w i

Tg =

i

g ,i

i

i

(9)

+ q API , polymer w API w polymer

i

i

The qAPI,polymer parameter was fitted to the experimentally-determined glass-transition temperatures of the water-free API/HPMCAS ASDs. For predicting the influence of RH on the glass-transition temperature in Eqs 7 – 9, the amount of absorbed water was calculated using Eq 2 and PC-SAFT. The pure-component properties ρi and Tg,i of the APIs, polymers, and water used in this work, and the parameters for the glass-transition temperature calculations are summarized in Table 4. The calculated glass-transition temperatures refer to the fully-amorphous formulations and do not consider recrystallization.

Table 4. Densities, glass-transition temperatures and binary Gordon-Taylor- and Kweiparameters for calculating the glass-transition temperature of ASD formulations NAP APAP ρi Tg,i (g/cm³) (°C) Ki qNAP,i Ki qAPAP,i NAP 1.2510 -811 APAP 1.2942 2532 22 11 PVP 1.25 168 0.601 0 0.697 0 PVPVA64 1.1952 11111 0.725 0 0.842 0 HPMCAS 1.28* 120* 0.659 -82** 0.764 -139** water 1.0043 -13843 2.455 - 2.849 *This work **Fitted to glass-transition temperatures of API/HPMCAS ASDs measured using DSC. The corresponding results for measurement and modeling are given in the Results section. component i



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MATERIALS & METHODS

Materials NAP and APAP (polymorphic form I) were purchased from Sigma-Aldrich (Steinheim, Germany). PVP (Kollidon 25) with an average molar mass of 25 700 g/mol and PVPVA64 (Kollidon VA 64) with an average molar mass of 65 000 g/mol were purchased from BASF (Ludwigshafen, Germany). HPMCAS (126G) with an average molar mass of 150 000 g/mol was purchased from Dow (Bomlitz, Germany). All substances were used as obtained without further purification.

Preparation of ASDs The NAP/HPMCAS- and APAP/HPMCAS-ASD formulations for the long-term stability studies were prepared by hot-melt extrusion (HME) using the HAAKE MiniCTW microconical twin screw compounder from Thermo Fisher Scientific (Dreieich, Germany). In a first step, the water content of HPMCAS was determined to be 2.05 wt % using the Moisture Analyzer HB43-S from Mettler Todelo (Greifensee, Switzerland). Afterwards, a total mass of 10 - 20 g of API and HPMCAS was mixed with API contents of 5, 10, 20, 40, and 60 wt % (water free), and extruded at 170 - 180 °C with 30 rpm rotation speed. The results of the longterm stability of the API/PVP and API/PVPVA64 (Table 5) were taken from a former work32. These formulations were also prepared by HME using the same extruder and comparable extrusion conditions (150 – 170 °C, 20 – 30 rpm). Preparing the ASDs with a similar method is important as kinetic stability can be affected by the method of preparation.53-55 In addition, API/HPMCAS-ASD formulations with 61 wt % APAP, 39 wt % APAP, and 60 wt % NAP were manufactured by spray drying for measuring the solubility of the APIs in the polymer and the glass-transition temperature of the corresponding amorphous formulations. A mini spray dryer B-290 with an inert-loop from Büchi (Essen, Germany) was used for the preparation. In total, 1 g of API and HPMCAS was dissolved in 100 mL acetone. 14 ACS Paragon Plus Environment

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With an inlet temperature of 62 °C the solution was fed to the spray dryer at a rate of 8 mL/min. Nitrogen was used as the drying gas at 601 L/h. The prepared samples were dried at 25 °C in vacuum oven for at least 48 hours to remove residual acetone or moisture absorbed from the environment. Due to the high API content of the spray-dried ASDs, they partially recrystallized into finely dispersed API crystals shortly after manufacturing. The recrystallized APIs were of the same polymorphic form as the starting API, which was confirmed by PXRD measurements. These recrystallized ASDs systems where used afterwards to measure the solubility temperature of the crystalline API in the polymer by DSC.

Measuring the API solubility in polymers and the glass-transition temperature of ASDs Solubility of NAP and APAP in HPMCAS and the glass-transition temperatures of the corresponding ASDs were measured by modulated differential scanning calorimetry (mDSC) using the Q2000 apparatus from TA Instruments (Eschborn, Germany). The DSC measurements were conducted with all spray dried API/HPMCAS formulations (61 wt % APAP, 39 wt % APAP, and 60 wt % NAP) and with the HME samples with 20 wt % APAP, 20 wt % NAP, and 40 wt % NAP. For each mDSC measurement, 5 – 10 mg of each sample was filled into a standard open aluminum pan and put into the measurement cell, which was purged with 50 mL/min of nitrogen. The following measurement method was applied: in a first step, the sample was heated from -10 °C to 190 °C with a heating rate of 1, 2, or 5 K/min and an amplitude of 0.159 K, 0.318 K or 0.795 K, respectively, at a modulation period of 60 s. It was then kept isothermal at 190 °C for 5 minutes before, in a second step, it was cooled with 10 K/min to 10 °C and kept isothermally at -10 °C for 5 min. In the third step, the sample was reheated to 190 °C with a heating rate of 10 K/min, a modulation period of 60 s and 1.590 K amplitude.



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During the first heating step, water which was absorbed from the environment was removed and the API recrystallized in samples with at least 39 wt % API. At higher temperatures, the crystalline API dissolved again, which was reflected by an endothermic peak in the total heat flow. The offset of the endothermic peak was considered as solubility temperature of the API in HPMCAS. This solubility temperature usually linearly depends on the heating rate. Therefore the equilibrium solubility temperature was determined by extrapolating the measurement results for 1, 2, and 5 K/min to 0 K/min. In none of the measured samples, a recrystallization peak could be observed in the total heat flow during cooling down (second step). Thus, the fully-amorphous sample was reheated in the third step, so that the glasstransition temperature of the ASD could be determined from the half height of the step in the signal of the reversing heat flow. The HME samples with 20 wt % API did not recrystallize. Thus, no solubility temperature could be determined. Therefore, 100 mg of a 20 wt % APAP sample was prepared by ball milling (Pulverisette 23, Fritsch, Idar-Oberstein, Germany) for 30 s at 50 Hz and the solubility temperature of APAP in HPMCAS was determined via DSC. This did not work for a 20 wt % NAP sample as the solubility temperature obviously was very close to the glass-transition temperature which did not allow for a reliable determination of the solubility temperature via DSC measurements at low NAP contents.

Long-term stability studies Analogous to the storage of PVP- and PVPVA64-based samples, which has been described in an earlier work32, milled NAP/HPMCAS and APAP/HPMCAS extrudates were stored at (1) 25 °C/0% RH in a vacuum chamber by Binder (Tuttlingen, Germany), (2) at 25 °C/60% RH in a storage chamber by Binder with a saturated aqueous sodium bromide solution, and (3) at 40 °C/75% RH in a WKL34 chamber by Weiss (ReiskirchenLindenstruth, Germany). After 0, 1, 3, 6, 9, 12, 15, and 18 months, powder X-ray diffraction 16 ACS Paragon Plus Environment

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(PXRD) measurements of the samples were conducted to distinguish between amorphous and crystalline ones. The benchtop X-ray diffractometer MiniFlex 600 of Rigaku (Ettlingen, Germany) was used for the PXRD-measurements, with the same method as applied earlier32 for PVP- and PVPVA64-ASD samples. If the resulting PXRD pattern showed a halo without defined peaks, the sample was categorized as PXRD amorphous. Conversely, defined peaks indicate presence of crystalline material in the sample, so that it was categorized as PXRD crystalline. By comparing the patterns of recrystallized samples to those of pure crystalline NAP or APAP (polymeric form I) the recrystallized domains were validated as API crystals.

RESULTS

Phase behavior of water-free HPMCAS-ASD formulations PC-SAFT pure-component parameters of all involved components (NAP, APAP and HPMCAS) required for calculating the solubility of APIs in HPMCAS can be found in Table 2: NAP- and APAP-PC-SAFT parameters were known from literature11,28 and those of HPMCAS were fitted to temperature- and concentration-dependent densities of HPMCAS solutions in ethyl acetate and RH-dependent water sorption by HPMCAS. The corresponding data and modeling results can be found in the Supporting Information. In addition, the solubilities of the two APIs in HPMCAS and the glass-transition temperatures of the corresponding fully-amorphous formulations were determined by DSC measurements. The experimental data for the solubility and glass-transition temperatures were correlated using PC-SAFT and the Kwei equation, respectively. The results are presented in Figure 3.



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Figure 3. Phase diagrams of water-free ASD formulations (a) APAP/HPMCAS and (b) NAP/HPMCAS. The triangles and squares show the solubility of the APIs in HPMCAS and the glass-transition temperature of the ASDs, respectively. The full lines represent the solubility lines calculated using PC-SAFT. The dashed lines represent the glass-transition temperatures calculated using the Kwei equation. The binary PC-SAFT parameters kij between each API and HPMCAS were fitted to the experimentally determined solubility temperatures by minimizing the average relative deviation (ARD, Eq 10) between experimental and calculated values. The parameters were determined to kAPAP,HPMCAS = 0.0196 (7.94% ARD) and kNAP,HPMCAS = -0.0289 (ARD 6.76%) for APAP/HPMCAS and NAP/HPMCAS, respectively. According to Eq 5, a positive kijvalue lowers the dispersion compared to the geometric mean of the pure-component dispersion-energy parameters, while a negative value leads to higher dispersion energy. Therefore the fitted interaction parameters (kAPAP,HPMCAS > 0 and kNAP,HPMCAS < 0) reveal that the van der Waals-attraction forces between NAP and HPMCAS are stronger than between APAP and HPMCAS.

ARD =

1 n exp tl

n exp tl

w calcd,i − w exp tl,i

i =1

w exp tl,i

∑

(10)

The Kwei-parameters qAPI.HPMCAS were fitted to the experimental data of the glass-transition temperatures resulting in -139 (37.53% ARD) for APAP/HPMCAS and -82 (27.73% ARD) for NAP/HPMCAS. The strongly negative values indicate weak specific interactions between the APIs and HPMCAS and strong self-association of the APIs.27,42 The qAPI.HPMCAS for 18 ACS Paragon Plus Environment

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APAP/HPMCAS is lower (more negative) than for NAP/HPMCAS, again indicating weaker specific interactions between APAP and HPMCAS than between NAP and HPMCAS. As Figure 3 shows a very good agreement between modeling and experimental data, PCSAFT and the Kwei equation obviously are appropriate models for calculating the phase behavior of the dry HPMCAS-ASD formulations.

Long-term physical stability of HPMCAS ASDs at humid conditions To account for the impact of RH on the phase behavior of the APAP/HPMCAS and NAP/HPMCAS ASDs, the water absorbed by the ASD formulations from humid environment as well as the solubility lines of the APIs in the resulting polymer/water mixture were predicted using PC-SAFT and by simultaneously solving Eqs 1 and 2. The water content predicted using PC-SAFT in Eq 2 assuming a fully-amorphous ASD formulation was

incorporated into the Kwei equation (Eq. 9) for predicting the glass-

transition temperature of the hypothetical crystal-free formulation at given RH. All parameters required for PC-SAFT and the Kwei equation are summarized in Table 1 to Table 4. Figure 4 shows the modeled (0% RH) and predicted (60% RH and 75% RH) phase diagrams in comparison with the results of stability studies of API/HPMCAS ASDs stored at 25 °C/0% RH, 25 °C/60% RH, and 40 °C/75% RH. Samples on or to the left of the solubility line are thermodynamically stable and expected to never recrystallize but to remain amorphous even at infinite storage time. Samples to the right of the solubility line will form API crystals during thermodynamic equilibration, but might remain amorphous for a long time, especially when they are stored at sufficient distance below the glass-transition temperature and/or close to the solubility line.



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Figure 4. Stability studies of HPMCAS ASDs at different storage conditions. (a) APAP/HPMCAS, 25 °C/0% RH, (b) NAP/HPMCAS, 25 °C/0% RH, (c) APAP/HPMCAS, 25 °C/60% RH, (d) NAP/HPMCAS, 25 °C/60% RH, (e) APAP/HPMCAS, 40 °C/75% RH, and (f) NAP/HPMCAS, 40 °C/75% RH. The full and dashed curves represent solubility and glass-transition temperature lines calculated using PC-SAFT and Kwei equation, respectively. The circles and stars reflect amorphous and recrystallized samples, respectively. The numbers on the symbols indicate the period in months, after which recrystallization was first observed by PXRD. The x-axis refers to the API content in the water-free ASD.


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The PC-SAFT predicted phase diagrams show that the solubility of NAP in HPMCAS is higher than the one of APAP at all storage conditions. The glass-transition temperature, and thus the kinetic stability is predicted to decrease with increasing API content in both systems at all storage conditions. Furthermore, the predicted solubility of both, APAP and NAP, slightly increased with increasing RH. Consequently, water was predicted to serve as a solubilizing agent for both APIs in HPMCAS. However, the impact of RH on the solubility curves at relevant storage temperatures (25 and 40 °C) was predicted to be negligible small, while the predicted glass-transition temperatures remarkably decreases with increasing RH. The predictions are in very good agreement with the experimental results of the long-term stability studies. Both APIs/HPMCAS ASDs with 60 wt % API recrystallized directly after extrusion. Also, the other physically-unstable samples recrystallized during the studies starting from those with highest API content. They show the highest degree of supersaturation as they are furthest from the solubility line as well as lowest kinetic stabilization due to low glass-transition temperature. Furthermore, API recrystallization occurred earlier in samples with lower API content when RH is increased. Comparing the results of the two APIs, it becomes obvious that at 25 °C/0% RH and at 25 °C/60% RH, the NAP ASDs show higher physical stability than the APAP ASDs. While the 20 wt % NAP/HPMCAS samples remained amorphous at 25 °C/0% RH throughout the 18 months-study, the corresponding APAP sample recrystallized within 9 months. At 25 °C/60% RH, both 20 wt % samples recrystallized, but APAP recrystallized within 6 months, while first NAP crystals were observed after 9 months. Although pure amorphous NAP recrystallizes faster than pure amorphous APAP42, the kinetically stabilized NAP/HPMCAS ASD tends to recrystallize slower than the APAP/HPMCAS ASD. A likely reason for this observation is the previously mentioned strong interaction between NAP and HPMCAS. In contrast, the APAP samples are more physically stable at accelerated conditions (40 °C/75% RH), because the 10 wt % NAP ASD recrystallized within 15 months, whereas 21 ACS Paragon Plus Environment


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the 10 wt % APAP ASD remained amorphous. It therefore seems that at high RH, where the ASDs absorb high moisture and kinetic stabilization is completely lost or very small, NAP cannot strongly interact with HPMCAS anymore and recrystallizes faster than APAP as expected.

Comparing the long-term physical stability of ASDs with different polymeric excipients Long-term stability studies of PVP- and PVPVA64-based ASDs similar to the studies with APAP/HPMCAS and NAP/HPMCAS presented above (Figure 4) as well as the corresponding calculations with PC-SAFT and the Gordon-Taylor equation have already been performed in a previous work.32 The modeled and predicted phase diagrams of the ASDs with the three different polymeric excipients at 0% RH, 60% RH, and 75% RH are shown in Figure 5 for each of the two APIs. The water sorption/API crystallization at 25 °C/60% RH and 40 °C/75% RH, which was again predicted with PC-SAFT, is shown in the Supporting Information in comparison to experimental data.


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Figure 5. Phase diagrams of ASDs at different storage conditions. (a) APAP-ASDs at 0% RH, (b) NAP-ASDs at 0% RH, (c) APAP-ASDs at 60% RH, (d) NAP-ASDs at 60% RH, (e) APAP-ASDs at 75% RH and (f) NAP-ASDs at 75% RH. Blue, gray, and black represent the different excipients PVP, PVPVA64, and HPMCAS, respectively. The full lines represent the solubility lines calculated using PC-SAFT. The dashed lines represent the glass-transition temperatures calculated using the Gordon-Taylor or Kwei equation. The x-axis refers to the API content in the water-free ASDs.



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As depicted in Figure 5, for the same API at the same relative humidity, the solubility and the glass-transition temperature depend on the polymeric excipients. It becomes obvious that the choice of the polymer has a remarkable impact on the ASD phase behavior and thus, on the physical stability of the ASD. The polymer impact on the physical stability is further discussed in the section “Discussions”. This was confirmed by long-term stability studies of APAP- and NAP-ASD formulations in all three polymers, PVP, PVPVA64, and HPMCAS, at 25 °C/0% RH, 25 °C/60% RH and 40 °C/75% RH. The results are summarized in Table 5. The storage time was separated into four periods: 0-1 months for indicating fast recrystallizing samples, 1-6 months, 6-12 months, and 12-18 months for distinguishing the extents of long-term physical stability. The samples are categorized as amorphous, PLM crystalline (PXRD amorphous) and PXRD crystalline. Distinguishing between PLM crystalline and amorphous samples was only possible for PVP- and PVPVA64-ASD formulations. In the HPMCAS-ASD samples, API-crystal detection by PLM was not possible due to depiction of birefringence in the pure HPMCAS matrix, which has been attributed to the semi-crystalline nature of the cellulosic backbone.56 Nevertheless, for the modeling, HPMCAS is assumed as fully-amorphous as no melting peak was detected when pure HPMCAS was heated in the DSC. Moreover, the pure HPMCAS was also found to be amorphous from PXRD measurements.


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Table 5. Results of long-term stability studies of APAP- and NAP-ASD formulations with PVP, PVPVA64 and HPMCAS as excipients at standardized ICH conditions. The numbers in the colored boxes indicate the API content in wt %. Green boxes represent completely amorphous ASD, while yellow and orange represent recrystallized ASD as detected by PLM and PXRD, respectively.



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DISCUSSION

Polymer impact on the physical stability of water-free ASD formulations According to the PC-SAFT modeling in Figure 5, APAP shows a very low solubility in dry HPMCAS compared to PVPVA64 and PVP. At room temperature (25 °C), the calculated APAP solubility in HPMCAS, PVPVA64 and PVP are 1.6 wt %, 27.8 wt %, and 32.0 wt %, respectively. The calculated NAP solubility in HPMCAS is 3 wt %, which is higher than the solubility of APAP in HPMCAS but still low compared to its solubility in PVPVA64 (20.7 wt %) and PVP (31.4 wt %). The calculated ASD glass-transition temperatures are highest in PVP for both APIs. This correlates with the high glass-transition temperature of 168 °C11 for pure PVP, which is 48 °C and 57 °C higher than the glass-transition temperatures of HPMCAS (120 °C) and PVPVA64 (111 °C11), respectively. The glass-transition temperature of the PVP ASDs was calculated with the Gordon-Taylor equation (Eq 7), which results in an approximately linear decrease with increasing API content due to the low glass-transition temperatures of the pure amorphous APIs (Tg,APAP = 25 °C32 and Tg,NAP = -8 °C11). Likewise, the glass-transition temperature of the PVPVA64 ASDs shows a similar trend with even lower glass-transition temperatures than the PVP ASDs. As described above, the glass-transition temperature of the HPMCAS-ASD formulations strongly deviates from the Gordon-Taylor prediction, which is reflected in the significantly negative Kwei-parameters qij. Therefore, at medium API contents the calculated glass-transition temperature of HPMCAS ASDs is much lower than the glasstransition temperature of the PVPVA64 ASDs, although the pure-component glass-transition temperature of HPMCAS is slightly higher than that of PVPVA64. Overall, the solubility of both APIs in the dry polymers as well the glass-transition temperatures of the water-free ASD formulations with API contents higher than 10 wt % increases in the following order: HPMCAS < PVPVA64 < PVP. This is in agreement with the experimental results of the 18-months long-term stability studies at 25 °C/0% RH (Table 5) 26 ACS Paragon Plus Environment

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which clearly show amorphous APAP up to 40, 30 and 10 wt % in PVP, PVPVA64, and HPMCAS, respectively. The NAP ASDs show a similar trend: maximum NAP contents of 40, 30 and 20 wt % were amorphously dissolved in PVP, PVPVA64, and HPMCAS, respectively, for 18 months at 25 °C/0% RH. Although still amorphous, it should be noted that compared to the PC-SAFT predicted solubility under this condition, these formulations are supersaturated. As pointed out already both, thermodynamic driving force for recrystallization and molecular mobility decrease as ASD composition moves closer to the solubility line and further from glass transition line. Consequently, kinetic stabilization is increased and propensity to recrystallize is decreased which permits such supersaturated ASD formulations to maintain their amorphous state for very long periods. For these same reasons, amorphous API recrystallized earlier in supersaturated HPMCAS ASDs than in PVPVA64 ASDs, and supersaturated PVPVA64 ASDs recrystallized earlier than PVP ASDs, when stored with the same API content under the same conditions. For example, the 40 wt % APAP/PVP ASD remains amorphous for at least 18 months at 25 °C/0% RH, while the same API content in PVPVA64 ASD recrystallized within 6 – 12 months and crystallization even took just 1-6 months in the case of HPMCAS ASD at the same conditions.

Influence of RH on the physical stability of ASD formulations with different polymeric excipients Figure 5 shows that the predicted glass-transition temperatures of the ASDs exposed to RH are remarkably lower than those of the dry ASDs. This phenomenon occurs due to the water uptake and the extremely low glass-transition temperature of water (-138 °C43). The glasstransition depression, due to increased RH, leads to convex curves for the PVP and PVPVA64 ASDs: while the glass-transition temperatures are lowest for the API-lean ASDs (left end of x-axis) and the polymer-lean ASDs (right of x-axis), the glass-transition temperatures reach a 27 ACS Paragon Plus Environment


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maximum at medium API content (30 – 50 wt %). Due to the high hydrophilicity of the polymers PVP and PVPVA64, their ASDs absorb a large amount of water at low API content resulting in a low glass-transition temperature. With increasing API content, the ASD becomes increasingly hydrophobic and water sorption decreases leading to an increase in the glass-transition temperature. However, at high API content the combined effect of the low polymer content and the significant plasticizing effect of the amorphous API results in lowering of the glass-transition temperature again. The RH impact on the glass-transition temperature is predicted to be stronger for the PVP formulations than for those with PVPVA64, which is due the higher water sorption of pure PVP compared to PVPVA64. The glass-transition temperatures of the HPMCAS ASDs show a different trend than those with PVP and PVPVA64: similar to the dry ASDs, the glass-transition temperature monotonously decreases with increasing API content. HPMCAS absorbs less water than PVP and PVPVA64 so that the difference between the water sorption of the amorphous APIs and the polymer is small. For this reason, the amount of absorbed water only weakly depends on the API content in the HPMCAS ASDs, thus depressing monotonously the glass-transition temperature as the API content increases. In correlation to the hydrophilicity of the polymers, the overall extent of the glass-transition depression compared to the dry state increases in the following order: HPMCAS < PVPVA64 < PVP. The decreasing kinetic stability with increasing RH, as a consequence of decreasing glass transition temperature, was also experimentally observed in the long-term stability studies of the ASDs: for each excipient type, the increasing number of orange boxes in Table 5 with increasing RH indicates that crystals were observed in more samples and after shorter periods at higher RH. At 40 °C/75% RH most samples were even stored above their glass-transition temperature, where kinetic stabilization due to the glassy state does not exist. This is the case for all thermodynamically-unstable samples of the PVP and PVPVA64 ASDs, which recrystallized mostly within a few weeks at 40 °C/75% RH, while at 25 °C/0% RH some 28 ACS Paragon Plus Environment

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thermodynamically-unstable samples remained amorphous for several months before first crystals could be observed. For instance, APAP/PVPVA64 ASD with 40 wt % API crystallized within one month at 40 °C/75% RH, but it took more than 6 months before first crystals were observed by PLM in the dry sample and another 6 months before crystals were detected via PXRD. Although the HPMCAS ASDs also recrystallized earlier with increasing RH, the period until first crystals were observed varies much less between the different storage conditions, than for PVP and PVPVA64 ASDs (Table 5). This confirms that kinetic stability of HPMCAS ASDs is less affected by RH than that of PVP and PVPVA64 ASDs. Comparison between the predicted solubility lines of APAP in the three polymers at humid conditions to the corresponding solubility lines in the dry polymers (Figure 5) shows that the APAP solubility at the relevant storage temperatures (25 °C or 40 °C) is not significantly affected by RH. Similar to the dry formulations, the solubility of APAP at 25 °C/60% RH and 40 °C/75% RH is predicted to be significantly higher in PVP and PVPVA64 (> 25 wt %) than in HPMCAS (< 5 wt %). Accordingly, APAP/PVP and APAP/PVPVA64 samples are stable up to 30 wt % APAP at all storage conditions throughout the 18-months study as shown in Table 5. In comparison, the HPMCAS ASD with 20 wt % APAP recrystallized within 1-6 months at 25 °C/60% RH and 40 °C/75% RH. This confirms a lower solubility of APAP in HPMCAS than in PVP and PVPVA64, especially at 40 °C/75% RH. This is also depicted in Figure 6, which shows the PXRD diffractograms of different APAP-ASD formulations stored at 40 °C/75% RH. The diffractograms of APAP/PVP and APAP/PVPVA64 ASDs with 30 wt % APAP show peak-free halos indicating fullyamorphous and thus, physically-stable ASD samples. In contrast, characteristic APAP peaks in the PXRD diffractogram of APAP/HPMCAS with 20 wt % APAP can be noticed. The characteristic APAP peaks were first observed after three months and became more intense during the 18-months storage.



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Figure 6. PXRD diffractograms of pure crystalline APAP (form I) and APAP ASDs stored at 40 °C/75% RH for 18 months

Overall, APAP/PVP and APAP/PVPVA64 ASDs with API contents of 30 wt % or less are more physically stable than the corresponding APAP/HPMCAS ASDs. The results of the long-term stability studies reveal that, the physical stability of the APAP-ASDs decreases in the order PVP > PVPVA64 > HPMCAS at all conditions, which is in accordance with the predicted solubility and glass-transition temperature lines. In contrast, the solubility of NAP in PVP and PVPVA64 was predicted to significantly decrease with increasing RH, while the solubility of NAP in HPMCAS was predicted to slightly increase. Nevertheless, the impact of RH on the NAP solubility in HPMCAS is negligibly small. The extent of the RH impact on the NAP solubility in the excipients again correlates with the polymer hydrophilicity and increases in the following order: HPMCAS < PVPVA64 < PVP. The predicted destabilizing effect of absorbed water on the NAP/PVP and NAP/PVPVA64 ASDs in contrast to the corresponding APAP ASDs was also experimentally observed: at humid storage, NAP/PVP samples of a similar API content recrystallized earlier than the corresponding APAP/PVP samples. The NAP/PVP sample with 25 wt % NAP recrystallized at 40 °C/75% RH within 6 – 12 months, while the 30 wt % 30 ACS Paragon Plus Environment

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APAP/PVP sample remained amorphous for 18 months (Figure 6). A similar trend can be observed for the PVPVA64-based formulations. At 40 °C/75% RH, the 30 wt % NAP/PVPVA64 sample recrystallized within the first month, while the 30 wt % APAP/PVPVA64 ASD was stable throughout the 18 months of storage. All NAP ASDs show low physical stability at 40 °C/75% RH. At these accelerated conditions, a maximum NAP content of only 15 wt% (NAP/PVPVA64) could be embedded in amorphous form without recrystallization within the 18-months long-term stability study. This corresponds to the PC-SAFT calculations predicting the solubility of NAP in all three polymers to be low at 40 °C/75% RH (< 5 wt %). The low physical stability of NAP ASDs at 40 °C/75% RH can be seen in the PXRD diffractograms in Figure 7. The diffractograms of the 25 wt % NAP/PVP, 30 wt % NAP/PVPVA64 and 10 wt % NAP/HPMCAS ASDs in Figure 7 exhibit NAP characteristic peaks indicating API recrystallization. The peaks of the NAP/HPMCAS diffractogram are less intense compared to the other samples because the low API content and hence, the recrystallized fraction is lower. Nevertheless, the small peaks in the diffractogram with positions coinciding with that of crystalline NAP clearly indicate NAP crystals in the 10 wt % NAP/HPMCAS sample. In summary, RH has a more negative effect on the physical stability of NAP ASDs than on the APAP ASDs, particularly when PVP or PVPVA64 is used as excipient. As described above, NAP shows a much lower solubility in water than APAP. For this reason absorbed water at humid conditions leads to a reduction of the overall solubility of NAP in the wet polymer compared to the water-free system, resulting in a lower thermodynamic stability.



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Figure 7. PXRD diffractograms of pure crystalline NAP and NAP ASDs stored at 40 °C/75% RH for 18 months

CONCLUSION The solubility of acetaminophen (APAP) and naproxen (NAP) in hydroxypropyl methylcellulose acetate succinate 126G (HPMCAS) and the glass-transition temperature of the corresponding ASDs was modeled using PC-SAFT and Kwei equation, respectively. PCSAFT was also used to predict the amount of absorbed water at humid storage conditions and thus to predict the impact of relative humidity (RH) on the phase behavior. The predictions were performed without using any experimental data of the humid ASD samples and compared to those of APAP and NAP ASDs with poly(vinylpyrrolidone) K25 (PVP) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) as excipients.32 Experimental physical stability studies at dry (25 C°/0% RH) and standardized ICH storage conditions (25 °C/60% RH and 40 °C/75% RH) were in good agreement with the predicted results. The studies have shown that at dry storage (0% RH), solubilizing and stabilizing abilities of the polymers increase in the following order: HPMCAS < PVPVA64 < PVP. RH has a small impact on APAP solubility in the polymers, but significantly reduces the glasstransition temperature of all the ASDs as well as NAP solubility in the polymers. The 32 ACS Paragon Plus Environment

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influence of RH on the physical stability is increasing with increasing hydrophilicity of the polymers (HPMCAS < PVPVA64 < PVP). For that reason the stability of amorphous NAP in all three polymers is low at high RH, while PVP- and PVPVA64-ASDs with APAP contents up to 30 wt % are thermodynamically stable and did not recrystallize even at accelerated conditions (40 °C/75% RH) throughout the 18 months of storage. All in all, PC-SAFT and the Kwei equation are worthwhile tools to predict the physical stability of ASDs and can be applied to optimize early phase development of ASD formulation as well as to reduce the number of time-consuming stability studies.

ASSOCIATED CONTENT

Supporting Information Fitting of PC-SAFT pure-component parameters of HPMCAS to densities of HPMCAS solutions in ethyl acetate and water sorption data. Measurement and calculation of water sorption in dependence of the polymer type and the ASD composition at 25 °C/60% RH and 40 °C/75% RH. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION

Corresponding Authors *

Tel.: +49-621-589-4940, Fax: +49-621-589-2070, Email: [email protected]

**

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Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.



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Funding Sources This study was funded by AbbVie. AbbVie participated in the study design, research, data collection, analysis and interpretation of data, as well as writing, reviewing, and approving the publication. S.K., O.H., M.D., and K.L. are AbbVie employees and may own AbbVie stock/options. G.S. is an employee at the Department for Biochemical and Chemical Engineering of the TU Dortmund University and has no conflict of interest to report. ABBREVIATIONS SL

a, Helmholtz energy (J); ∆cp,0,API , difference in the solid and liquid heat capacities of the SL

pure API (J/molK); ∆h 0,API , enthalpy of fusion of the pure API (J/mol); kB, Boltzmann constant; kij, PC-SAFT binary interaction parameter; K, Gordon-Taylor binary parameter; m, mass (g); mseg, segment number; M, molar mass (g/mol); Nassoc, number of association sites; p, pressure (Pa); qij, Kwei binary interaction parameter; R, universal gas constant SL

(8.1345 J mol-1 K-1); T, temperature (K); T0,API, melting temperature of the pure API (K), Tg, glass-transition temperature (K); u/kB dispersion-energy parameter; w, content (wt%); x, mole fraction; γ, activity coefficient; εAiBi/kB association-energy parameter, κAiBi, associationvolume parameter; ρ, density (g/cm³); σ, segment diameter; 0, pure component; Ai, Bi, association sites A and B of molecule i; API, active pharmaceutical ingredient; assoc, association; b, intercept; calcd, calculated; disp, dispersion; exptl, experimental; hc, hard chain; i, j, component indices; L, liquid phase; LV, liquid-vapor; m, slope; res, residual; S, solid phase; seg, segment; SL, solid-liquid; V, vapor; APAP, acetaminophen; API, active pharmaceutical ingredient; ARD, average relative deviation; ASD, amorphous solid dispersion; DSC, differential scanning calorimetry; HME, hot melt extrusion; HPMCAS, hydroxypropyl methylcellulose acetate succinate 126G; NAP, 34 ACS Paragon Plus Environment

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naproxen; ICH, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; mDSC, modulated differential scanning calorimetry; PCSAFT, Perturbed-Chain Statistical Associating Fluid Theory; PLM, polarized light microscope; PVP, poly(vinylpyrrolidone) (Kollidon 25); PVPVA64, poly(vinylpyrrolidoneco-vinyl acetate) (VA64); PXRD, powder X-ray diffraction; RH, relative humidity; SLE, solid-liquid equilibrium; VLE, vapor-liquid equilibrium

REFERENCES (1)

Leuner, C.; Dressman, J. Improving drug solubility for oral delivery using solid dispersions.

Eur. J. Pharm. Biopharm. 2000, 50, 47–60. (2)

Vasconcelos, T.; Sarmento, B.; Costa, P. Solid dispersions as strategy to improve oral

bioavailability of poor water soluble drugs. Drug discovery today. 2007, 12, 1068–1075. (3)

Chiou, W. L.; Riegelman, S. Pharmaceutical Applications of Solid Dispersion Systems. J.

Pharm. Sci. 1971, 60, 1281–1302. (4)

Murdande, S. B.; Pikal, M. J.; Shanker, R. M.; Bogner, R. H. Solubility advantage of

amorphous pharmaceuticals: I. A thermodynamic analysis. J. Pharm. Sci. 2010, 99, 1254–1264. (5)

Paus, R.; Ji, Y.; Vahle, L.; Sadowski, G. Predicting the Solubility Advantage of Amorphous

Pharmaceuticals: A Novel Thermodynamic Approach. Mol. pharmaceutics. 2015, 12, 2823–2833. (6)

Baghel, S.; Cathcart, H.; O'Reilly, N. J. Polymeric Amorphous Solid Dispersions: A Review

of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs. J. Pharm. Sci. 2016, 105, 2527–2544. (7)

Kadajji, V. G.; Betageri, G. V. Water Soluble Polymers for Pharmaceutical Applications.

Polymers. 2011, 3, 1972–2009.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(8)

Curatolo, W.; Nightingale, J. A.; Herbig, S. M. Utility of hydroxypropylmethylcellulose

acetate succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI milieu.

Pharm. Res. 2009, 26, 1419–1431. (9)

Matsumoto, T.; Zografi, G. Physical Properties of Solid Molecular Dispersions of

Indomethacin with Poly(vinylpyrrolidone) and Poly(vinylpyrrolidone-co-vinylacetate) in Relation to Indomethacin Crystallization. Pharm. Res. 1999, 16, 1722–1728. (10) Paudel, A.; van Humbeeck, J.; van den Mooter, G. Theoretical and experimental investigation on the solid solubility and miscibility of naproxen in poly(vinylpyrrolidone). Mol. pharmaceutics.

2010, 7, 1133–1148. (11) Prudic, A.; Kleetz, T.; Korf, M.; Ji, Y.; Sadowski, G. Influence of copolymer composition on the phase behavior of solid dispersions. Mol. pharmaceutics. 2014, 11, 4189–4198. (12) Yuan, X.; Xiang, T.-X.; Anderson, B. D.; Munson, E. J. Hydrogen Bonding Interactions in Amorphous Indomethacin and Its Amorphous Solid Dispersions with Poly(vinylpyrrolidone) and Poly(vinylpyrrolidone-co-vinyl acetate) Studied Using (13)C Solid-State NMR. Mol. pharmaceutics.

2015, 12, 4518–4528. (13) Forster, A.; Hempenstall, J.; Rades, T. Characterization of glass solutions of poorly watersoluble drugs produced by melt extrusion with hydrophilic amorphous polymers. J. Pharm.

Pharmacol. 2001, 53, 303–315. (14) Ji, Y.; Paus, R.; Prudic, A.; Lubbert, C.; Sadowski, G. A Novel Approach for Analyzing the Dissolution Mechanism of Solid Dispersions. Pharm. Res. 2015, 32, 2559–2578. (15) Paus, R.; Prudic, A.; Ji, Y. Influence of excipients on solubility and dissolution of pharmaceuticals. Int. J. Pharm. 2015, 485, 277–287. (16) Al-Obaidi, H.; Lawrence, M. J.; Al-Saden, N.; Ke, P. Investigation of griseofulvin and hydroxypropylmethyl cellulose acetate succinate miscibility in ball milled solid dispersions. Int. J.

Pharm. 2013, 443, 95–102. (17) Friesen, D. T.; Shanker, R.; Crew, M.; Smithey, D. T.; Curatolo, W. J.; Nightingale, J. A. S. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol.

pharmaceutics. 2008, 5, 1003–1019. 36 ACS Paragon Plus Environment

Page 36 of 41

Page 37 of 41

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(18) Trasi, N. S.; Taylor, L. S. Dissolution performance of binary amorphous drug combinations-Impact of a second drug on the maximum achievable supersaturation. Int. J. Pharm. 2015, 496, 282– 290. (19) Jackson, M. J.; Kestur, U. S.; Hussain, M. A.; Taylor, L. S. Dissolution of Danazol Amorphous Solid Dispersions: Supersaturation and Phase Behavior as a Function of Drug Loading and Polymer Type. Mol. pharmaceutics. 2016, 13, 223–231. (20) Konno, H.; Handa, T.; Alonzo, D. E.; Taylor, L. S. Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur. J. Pharm. Biopharm. 2008, 70, 493–499. (21) Prudic, A.; Ji, Y.; Sadowski, G. Thermodynamic phase behavior of API/polymer solid dispersions. Mol. pharmaceutics. 2014, 11, 2294–2304. (22) Hancock, B. C.; Shamblin, S. L.; Zografi, G. Molecular Mobility of Amorphous Pharmaceutical Solids Below Their Glass Transition Temperatures. Pharm. Res. 1995, 12, 799–806. (23) Rumondor, A. C. F.; Marsac, P. J.; Stanford, L. A.; Taylor, L. S. Phase behavior of poly(vinylpyrrolidone) containing amorphous solid dispersions in the presence of moisture. Mol.

pharmaceutics. 2009, 6, 1492–1505. (24) Xie, T.; Taylor, L. S. Effect of Temperature and Moisture on the Physical Stability of Binary and Ternary Amorphous Solid Dispersions of Celecoxib. J. Pharm. Sci. 2016. (25) Prudic, A.; Ji, Y.; Luebbert, C.; Sadowski, G. Influence of humidity on the phase behavior of API/polymer formulations. Eur. J. Pharm. Biopharm. 2015, 94, 352–362. (26) Gross, J.; Sadowski, G. Perturbed-Chain SAFT. Ind. Eng. Chem. Res. 2001, 40, 1244–1260. (27) Kwei, T. K. The effect of hydrogen bonding on the glass transition temperatures of polymer mixtures. J. Polym. Sci. B Polym. Lett. Ed. 1984, 22, 307–313. (28) Ruether, F.; Sadowski, G. Modeling the solubility of pharmaceuticals in pure solvents and solvent mixtures for drug process design. J. Pharm. Sci. 2009, 98, 4205–4215. (29) Paus, R.; Ji, Y.; Braak, F.; Sadowski, G. Dissolution of Crystalline Pharmaceuticals. Ind. Eng.

Chem. Res. 2015, 54, 731–742.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(30) Gross, J.; Spuhl, O.; Tumakaka, F.; Sadowski, G. Modeling Copolymer Systems Using the Perturbed-Chain SAFT Equation of State. Ind. Eng. Chem. Res. 2003, 42, 1266–1274. (31) Tumakaka, F.; Gross, J.; Sadowski, G. Modeling of polymer phase equilibria using PerturbedChain SAFT. Fluid Phase Equilib. 2002, 194-197, 541–551. (32) Lehmkemper, K.; Kyeremateng, S.; Heinzerling, O.; Degenhardt, M.; Sadowski, G. Long-term physical stability of PVP- and PVPVA-amorphous solid dispersions. Mol. pharmaceutics. 2016, 14, 157-171 (33) Caron, V.; Hu, Y.; Tajber, L.; Erxleben, A.; Corrigan, O. I.; McArdle, P.; Healy, A. M. Amorphous solid dispersions of sulfonamide/Soluplus® and sulfonamide/PVP prepared by ball milling. AAPS PharmSciTech. 2013, 14, 464–474. (34) Qian, F.; Wang, J.; Hartley, R.; Tao, J.; Haddadin, R.; Mathias, N.; Hussain, M. Solution behavior of PVP-VA and HPMC-AS-based amorphous solid dispersions and their bioavailability implications. Pharm. Res. 2012, 29, 2765–2776. (35) Marsac, P. J.; Li, T.; Taylor, L. S. Estimation of drug-polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm. Res.

2009, 26, 139–151. (36) Sun, Y.; Tao, J.; Zhang, G. G. Z.; Yu, L. Solubilities of crystalline drugs in polymers: an improved analytical method and comparison of solubilities of indomethacin and nifedipine in PVP, PVP/VA, and PVAc. J. Pharm. Sci. 2010, 99, 4023–4031. (37) Wlodarski, K.; Sawicki, W.; Kozyra, A.; Tajber, L. Physical stability of solid dispersions with respect to thermodynamic solubility of tadalafil in PVP-VA. Eur. J. Pharm. Biopharm. 2015, 96, 237– 246. (38) Gordon, M.; Taylor, J. S. Ideal copolymers and the second-order transitions of synthetic rubbers. i. non-crystalline copolymers. J. Appl. Chem. 1952, 2, 493–500. (39) Hancock, B. C.; Zografi, G. Characteristics and significance of the amorphous state in pharmaceutical systems. J. Pharm. Sci. 1997, 86, 1–12.


Page 38 of 41

Page 39 of 41

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(40) Kalogeras, I. M. A novel approach for analyzing glass-transition temperature vs. composition patterns: application to pharmaceutical compound+polymer systems. Eur. J. Pharm. Sci. 2011, 42, 470–483. (41) Lin, A. A.; Kwei, T. K.; Reiser, A. On the physical meaning of the Kwei equation for the glass transition temperature of polymer blends. Macromolecules. 1989, 22, 4112–4119. (42) Nair, R.; Nyamweya, N.; Gönen, S.; Martı́nez-Miranda, L. J.; Hoag, S. W. Influence of various drugs on the glass transition temperature of poly(vinylpyrrolidone). Int. J. Pharm. 2001, 225, 83–96. (43) Hancock, B. C.; Zografi, G. The Relationship Between the Glass Transition Temperature and the Water Content of Amorphous Pharmaceutical Solids. Pharm. Res. 1994, 11, 471–477. (44) Hoffman, J. D. Thermodynamic Driving Force in Nucleation and Growth Processes. J. Chem.

Phys. 1958, 29, 1192. (45) Kyeremateng, S. O.; Pudlas, M.; Woehrle, G. H. A fast and reliable empirical approach for estimating solubility of crystalline drugs in polymers for hot melt extrusion formulations. J. Pharm.

Sci. 2014, 103, 2847–2858. (46) Mohan, R.; Lorenz, H.; Myerson, A. S. Solubility measurement using differential scanning calorimetry. Ind. Eng. Chem. Res. 2002, 41, 4854–4862. (47) Prausnitz, J. M.; Lichtenthaler, R. N.; Azevedo, E. G. d. Molecular thermodynamics of fluid-

phase equilibria; Prentice-Hall: Englewood Cliffs, N.J., 1986. (48) Granberg, R. A.; Rasmuson, Å. C. Solubility of Paracetamol in Pure Solvents. J. Chem. Eng.

Data. 1999, 44, 1391–1395. (49) Gross, J.; Sadowski, G. Application of the Perturbed-Chain SAFT Equation of State to Associating Systems. Ind. Eng. Chem. Res. 2002, 41, 5510–5515. (50) Cameretti, L. F.; Sadowski, G. Modeling of aqueous amino acid and polypeptide solutions with PC-SAFT. Chem. Eng. Process. 2008, 47, 1018–1025. (51) Paus, R. Solubility and Dissolution of Pharmaceuticals; PhD thesis. Dr. Hut: München, 2016.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(52) Six, K.; Verreck, G.; Peeters, J.; Brewster, M.; van den Mooter, G. Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers. J. Pharm. Sci. 2004, 93, 124–131. (53) Patterson, J. E.; James, M. B.; Forster, A. H.; Lancaster, R. W.; Butler, J. M.; Rades, T. Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling. Int. J. Pharm. 2007, 336, 22–34. (54) Guns, S.; Dereymaker, A.; Kayaert, P.; Mathot, V.; Martens, J. A.; van den Mooter, G. Comparison between hot-melt extrusion and spray-drying for manufacturing solid dispersions of the graft copolymer of ethylene glycol and vinylalcohol. Pharm. Res. 2011, 28, 673–682. (55) Agrawal, A. M.; Dudhedia, M. S.; Patel, A. D.; Raikes, M. S. Characterization and performance assessment of solid dispersions prepared by hot melt extrusion and spray drying process.

Int. J. Pharm. 2013, 457, 71–81. (56) Sarode, A. L.; Obara, S.; Tanno, F. K.; Sandhu, H.; Iyer, R.; Shah, N. Stability assessment of hypromellose acetate succinate (HPMCAS) NF for application in hot melt extrusion (HME).

Carbohydr. Polym. 2014, 101, 146–153.


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For Table of Contents Use Only Title: Impact of Polymer Type and Relative Humidity on the Long-Term Physical Stability of Amorphous Solid Dispersions

Authors: Kristin Lehmkemper, Samuel O. Kyeremateng, Oliver Heinzerling, Matthias Degenhardt and Gabriele Sadowski


Impact of Polymer Type and Relative Humidity on ... - ACS Publications

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