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Long-term physical stability of PVP- and PVPVA-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.6b00763 • Publication Date (Web): 18 Nov 2016 Downloaded from http://pubs.acs.org on November 28, 2016

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Molecular Pharmaceutics

Long-term physical stability of PVP- and PVPVAamorphous solid dispersions Kristin Lehmkemper1,2, Samuel O. Kyeremateng1,*, Oliver Heinzerling1, Matthias Degenhardt1, 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, phase behavior, long-term stability studies, relative humidity, thermodynamic model, Flory-Huggins, PC-SAFT, acetaminophen, naproxen, polymer

ACS Paragon Plus Environment

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ABSTRACT The preparation of amorphous solid dispersion (ASD) formulations is a promising strategy to improve the bioavailability of an active pharmaceutical ingredient (API). By dissolving the API in a polymer it is stabilized in its amorphous form, which usually shows higher water solubility than its crystalline counterpart. To prevent recrystallization, the long-term physical stability of ASD formulations is of big interest. In this work, the solubility of the APIs acetaminophen and naproxen in the excipient polymers poly(vinyl pyrrolidone) (PVP K25) and poly(vinyl pyrrolidone-co-vinyl acetate) (PVPVA64) was calculated with three models: the PerturbedChain Statistical Associating Fluid Theory (PC-SAFT), the Flory-Huggins model (FH) and an empirical model (Kyeremateng et al., J. Pharm. Sci, 2014, 103, 2847–2858). PC-SAFT and FH were further used to predict the influence of relative humidity (RH) on the API solubility in the polymers. The Gordon-Taylor equation was applied to model the glass-transition temperature of dry ASD and at humid conditions. The calculations were validated by 18 months-long stability studies at standardized storage conditions, 25 °C/0% RH, 25 °C/60% RH, and 40 °C/75% RH. The results of the three modeling approaches for the API solubility in polymers agreed with the experimental solubility data, which are only accessible at high temperatures in dry polymers. However, at room temperature FH resulted in a lower solubility of the APIs in the dry polymers than PC-SAFT and the empirical model. The impact of RH on the solubility of acetaminophen was predicted to be small, but naproxen solubility in the polymers was predicted to decrease with increasing RH with both, PC-SAFT and FH. At 25 °C/60% RH and 40 °C/75% RH, PC-SAFT is in agreement with all results of the long-term stability studies, while FH underestimates the acetaminophen solubility in PVP K25 and PVPVA64.


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INTRODUCTION Low water solubility of new active pharmaceutical ingredients (APIs) is the main bottleneck in the development of solid oral dosage forms1-3. The preparation of amorphous solid dispersions (ASDs) is a promising technique to overcome this issue and to increase the bioavailability of the API4-6. ASDs consist of the amorphous form of an API molecularly dispersed in a hydrophilic polymeric matrix. The amorphous API has a higher energy level than its crystalline counterpart, which leads to a higher solubility in water compared to the crystalline form7-9. Because of its high energy level, the metastable amorphous form also has a high propensity to recrystallize10,11. The aim of molecularly dispersing the API in a polymeric matrix of high glass transition temperature is twofold. As long as the API concentration in the polymer matrix does not exceed the API solubility in the polymer, the ASD is thermodynamically stable and the API will never crystallize. Even if the API concentration is higher than its solubility, the molecular mobility of the API is reduced by the polymer matrix -in particular below the ASD glass-transition temperature- thus, inhibiting recrystallization (kinetic stability) and maintaining the solubility advantage of the amorphous form during the shelf-life of the formulation12-14. The presence of the polymer also improves the wettability and dissolution rate of the API in aqueous medium, which usually lead to increased bioavailability4,15. For the preparation of crystal-free ASDs by a non-solvent based process, such as hot melt extrusion, and the evaluation of the long-term physical stability of ASDs, the phase diagram of the API/polymer-system is of big interest. The physical stability comprises two contributions, the thermodynamic stability, which corresponds to the solubility of the API in the polymer matrix, as


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well as the kinetic stability, which is determined by the glass-transition temperature of the ASD. In Figure 1, a schematic phase diagram of an API/polymer-system is shown16.

Figure 1. Typical phase behavior scheme of an API/polymer system. The orange curve represents the solubility of the API in the polymer and the green curve the glass-transition temperature of the ASD. The curves divide the phase diagram into the following areas: (I) thermodynamically stable melt, (II) thermodynamically stable glass, (III) kinetically stable glass and (IV) thermodynamically and kinetically unstable melt.

The solubility is defined as the maximum API content which can be dissolved in the polymer at a certain temperature16. Therefore, the solibility line in Figure 1 devides the phase diagram into a thermodynamically stable and a thermodynamically unstable section: at a given temperature, an ASD is thermodynamically stable (will not crystallize) when the API content is lower than its solubility in the polymer (areas I and II in Figure 1). In turn, for a fixed API content the solubility line provides the temperature at which this API content can be completely dissolved in the polymer, which is usually determined by DSC measurements16. When the API content exceeds its solubility in the polymer at the given temperature (areas III and IV in Figure 1), the ASD is supersaturated and API recrystallization is likely to occur. However, if the storage


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temperature is sufficiently lower than the glass-transition temperature (area III in Figure 1), the molecular mobility of the API may be slowed enough to inhibit recrystallization at least for pharmaceutically-relevant time periods12,17. Such formulations are the so-called kineticallystabilized ASDs. As mentioned above, solubility temperatures of APIs in polymers are usually determined by differential scanning calorimetry (DSC)18,19 and only accessible in dry polymers and only at high API contents resulting in temperatures significantly higher than the glass transition of the polymer20. Therefore, at room temperature or other common storage temperatures, which are usually below the glass-transition temperature of the ASD, as well as for ASD formulations exposed to RH, time consuming long-term stability studies are necessary to assess the physical stability of the ASD. In these long-term studies, ASD samples of known composition are stored at defined conditions (temperature, RH) and investigated from time to time with respect to crystallization. In thermodynamic equilibrium at a given temperature, all ASD samples left of the solubility line are expected to be amorphous, while all samples to the right of the solubility line are expected to (finally) crystallize. Thus, the solubility line can be localized (at least after very long time) as being left of all crystallized samples. The experimental efforts and resources for those studies can be reduced by applying thermodynamic models to access the solubility of APIs in polymers at storage conditions. A common and widely applied model for this purpose is the Flory-Huggins (FH) model21,22. Although this was initially developed for polymer solutions21,22, it has already been successfully applied to API/polymer systems in several works19,23-29. Nevertheless, for some systems it was found that FH-modeling does not fit the experimental data19,26,30. Sun and coworkers19 reported


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inadequacy of FH for the description of the solubility of mannitol in PVP, and Sawicki and coworkers26 showed a poor fit of FH for the Tadalfil/PVPVA64 system. Alternative methods for the calculation of the API solubility in polymers are an empirical model by Kyeremateng et al.17 and the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT)31. PC-SAFT is an equation of state widely used in literature for systems containing all types of substances, including solids32,33, polymers34,35 and solvents32,33,36, and was recently also successfully applied to ASD formulations16,37,38. The aim of this work is the comparison of three models namely, FH21,22, PC-SAFT31, and the empirical model by Kyeremateng et al.17, for predicting the solubility of an API in a polymer under experimentally inaccessible conditions. Typically, both thermodynamic and kinetic stability of an ASD formulation is very dependent on temperature and moisture conditions of the storage environment. In this work the phase behavior of the water-free ASDs was calculated using the three models and the influence of relative humidity (RH) was predicted using PC-SAFT and FH. In contrast to the empirical model, FH and PC-SAFT are physically based models and consider pure-component properties of all components present as well as the intermolecular forces between these components. In particular PC-SAFT which (in contrast to the empirical model and FH) explicitely accounts for the formation of hydrogen bonds allows to predict the influence of water on the phase behavior of the ASDs from a physical perspective. The predictions were validated by long-term stability studies conducted for 18 months. As already stated above, supersaturated ASDs -to the right of the solubility line- can recrystallize, while samples to the left of the solubility line remain amorphous also for infinitively long storage time. Nevertheless, kinetic limitations determined by glass-transition temperature and other thermophysical properties have to be considered, when conclusions on the API solubility in the


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polymers are drawn based on the results of stability studies. Stability studies for such a long period are rare in literature, although they are the only reliable way to validate the predicted physical stability of ASDs by modeling tools. Naproxen and acetaminophen were selected as model APIs for these studies. The widely used commercial excipient polymers poly(vinyl pyrrolidone) (PVP K25) and poly(vinyl pyrrolidoneco-vinyl acetate) (PVPVA64) were used to prepare the ASD formulations. The chemical structures of the APIs and the polymers are shown in Figure 2.

(a)

(b)

(c)

(d)

Figure 2. Chemical structures of acetaminophen (a), naproxen (b), PVP (c) and PVPVA64 (n:m = 6:4 (w/w)) (d).

MODELING Calculation of API solubility (SLE) The solubility of an API in a polymer is calculated as a thermodynamic solid-liquid equilibrium (SLE). While the liquid phase (L) consists of the polymer and the dissolved API, the


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solid phase (S) is assumed to be pure crystalline API. In equilibrium the chemical potential of the API in the solid phase equals the chemical potential of the API in the liquid phase. This results in the solubility equation for calculating the maximum mole fraction of API, which can be dissolved in a polymer, x LAPI 39: x LAPI =

1 γ LAPI

 ∆h SL 0 , API exp  − RT 

 T 1 − SL  T 0 , API 

 ∆cSL  − p , 0 , API  R 

  T0SL, API  ln    T  

  T0SL, API  − + 1   T  

(1)

T is the temperature in Kelvin and R the universal gas constant (8.1345 J mol-1 K-1). The SL SL melting properties of the API, including melting temperature T0,API, heat of fusion ∆h 0,API and SL

difference in the solid and liquid heat capacities ∆cp,0,API , are taken from literature and are SL summarized in Table 1. In former works about the FH model ∆cp,0,API was usually neglected19,24–

27

. This corresponds to a simplification of the solubility equation (Eq 1). In this work, the

40 ∆cSL p,0,API was taken into consideration, to make the solubility calculations more accurate .

To consider deviations from ideal behavior, the activity coefficient of the API in the liquid phase γ LAPI is calculated with PC-SAFT or FH as described below. Table 1. Melting properties of naproxen and acetaminophen

T0SL ,API

API

(K)

∆hSL 0,API

∆cSL p,0,API

Ref.

(kJ/mol) (J/(mol·K))

429.47

31.5

87.44

41

acetaminophen 443.60

27.1

99.80

42

naproxen


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Calculation of the influence of RH on the API solubility (VSLE) To predict the influence of RH on the API solubility, three phases have to be considered, a vapor (V), a solid (S) and a liquid phase (L). As the vapor pressures of APIs and polymers are small compared to the vapor pressure of water, the vapor phase can be assumed to consist of pure water. The solid phase is still considered as pure crystalline API. The liquid phase is a mixture of water, polymer and dissolved (amorphous) API. Based on these assumptions, the API solubility in a mixture of polymer and absorbed water is calculated with Eq 1. The RH, which is defined as the ratio of the water partial pressure in the vapor phase pVwater and the vapor pressure of pure water pLV water at the same temperature, is calculated with RH =

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

(2)

x Lwater and γ Lwater are the mole fraction and the activity coefficient of water in the liquid phase, respectively. Using Eqs 1 and 2, the amount of absorbed water x Lwater as well as the solubility of the API in the polymer/water mixture x LAPI are calculated simultanously for a given temperature and RH. The activity coefficient of water in the liquid phase γ Lwater and the activity coefficient of the API in the liquid phase γ LAPI are calculated using PC-SAFT or FH. Hereafter, these two concepts as well as the empirical model for calculating the API solubility in dry polymer are introduced.

PC-SAFT According to PC-SAFT (Perturbed-Chain Statistical Associating Fluid Theory), the residual res hc Helmholtz energy a is obtained as a sum of a hard-chain reference term a and different


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perturbation contributions, as presented in Eq 331,34. Relevant contributions for the components disp assoc (polymers, APIs and water) used in this work are the dispersion a and the association a 34.

The concept of PC-SAFT is shortly presented below. The detailed terms for modeling with PCSAFT have already been described in previous works16,31,33. a res = a hc + a disp + a assoc

(3)

To obtain the different Helmholtz-energy contributions in Eq 3 each molecule of a component i is assumed to be a chain of m seg spherical segments of the same diameter σi . Segment number i hc and segment diameter σi are used to calculate the hard-chain contribution a , which m seg i disp accounts for repulsive forces between the molecules. The contribution a for van der Waals

attraction forces between the segments of different molecules depends on the dispersion-energy assoc parameter u i k B , where k B is the Boltzmann constant. The association contribution a

accounts for hydrogen bonding between the molecules and is characterized by the associationenergy parameter ε

AiBi

k B and the association-volume parameter κ AiBi . In total five pure-

component parameters are necessary34. Moreover, the number of association sites N iassoc (electron acceptors and electron donators) is determined from the molecular structure of the component. These parameters were taken from literature for the APIs, naproxen and acetaminophen,33,37 and for PVP K2538. PVPVA64 is a copolymer containing of vinylpyrrolidone and vinyl acetate monomers. The PC-SAFT parameters of the corresponding homopolymers PVP and polyvinyl acetate are available in literature38,43, so that the parameters of PVPVA64 were calculated based on a group contribution method44 from the homopolymer parameters. Besides the pure-component parameters, a binary interaction parameter kij is introduced to correct the dispersion energy u i k B in a mixture of component i and component j using Eq 4.


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u ij = (1 − k ij ) u i u j

(4)

kij might depend on the temperature as follows

k ij = k ij,slope ⋅ T(K ) + k ij,int ercept

(5)

The binary interaction parameter kAPI,polymer between the API and the polymer was fitted to experimental solubility data of the API in the polymers presented in the results section of this work (Table 6). To extend the model to a water-containing system, the interaction between each ASD compound and water has to be considered. The pure-component parameters of the used substances as well as the interaction parameters between each component i and water ki,water are summarized in Table 2. Table 2. PC-SAFT parameters of naproxen, acetaminophen, PVP K25, PVPVA64, and water component i

naproxen

ui kB

ε AiBi

 mol    (Å)  g 

(K)

0.0352

2.939

229.450

a

a

a

0.0498

3.508

398.284 1994.2

c

c

c

Mi

m seg i Mi

 g     mol  230.26

acetaminophe 151.16 n

σi

κAiBi

N assoc i

ki,water

(K)

(-)

(-)

(-)

934.2a

0.02a

2/2a

0.000227·T( K) -0.0612b

c

0.01c

2/2c

0.000177·T( K) -0.0505d

0e

0.02e

e

0f

0.02f

kB

PVP K25

25700

0.0407

2.710

205.599

e

e

e

PVPVA64

65000

0.0372

2.947

205.271

f

f

f

water

18.02

0.0669

2.793

353.945 2425.7

0.0451

h

h

h

h

h

231/231 653/653

-0.148e

f

-0.156g

1/1h

-

Prudic et al. 201437, bPaus et al. 2015.41, cRuether and Sadowski 2009.33, dPaus 201645, ePrudic et al. 2015.38, fCalculated with a group contribution method44 from parameters of PVP K2538 and polyvinyl acetate43, gFitted to water sorption data from literature38, hCameretti and Sadowski46 a


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The activity coefficient γ iL is defined as the ratio of the fugacity coefficient φ iL of the L

component i in the mixture and its pure-component fugacity coefficient φ 0i : L i

γ =

ϕ iL

(6)

ϕ 0Li

The fugacity coefficient is calculated with:

µ ires (T, v) ln γ = − ln Z k BT L i

(7)

µ ires is the residual chemical potential depending on temperature T, molar volume v as well as on the composition of the system. Z is the compressibility factor, which is defined as

Z=

pv k B NAVT

(8)

where N AV is the Avogadro number and p the system pressure. The residual chemical potential in Eq 7 is calculated from the residual Helmholtz energy (Eq 3) using: res  ∂(a res k BT  N  ∂(a res k BT  µires a   − ∑  = + Z − 1 +   ∂x  k B T k BT ∂ x j = 1 i j    

(9)

The activity coefficient γ iL is calculated with Eqs 6 – 9 and used to calculate the vapor-liquid equilibrium (Eq 2) as well as the solid-liquid equilibrium (Eq 1) in a system of two or more components.


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Flory-Huggins The FH model was initially developed for polymer solutions by Flory21 and Huggins22. Nowadays, it also became a common model to predict the thermodynamic stability of ASDs19,23– 29

. The activity coefficient γ iL of component i in the liquid phase is described by

ln γ iL = 1 + ln

ri ri − + χ ijΦ 2j r r

(10)

where Φ j is the volume fraction of component j in a binary mixture of the components i and j.

χij is the binary interaction parameter, which is fitted to experimental data, and might be temperature dependent as expressed in Eq 11. (11)

χ ij = χ 0 + χ 1 T

ri is the segment number of component i, which is calculated from pure-component properties with

ri =

Miρ1 M1ρi

(12)

M and ρ are molar mass and density, respectively, of the components i and 1, where component 1 is defined as the smaller molecule in the binary mixture. r is calculated using Eq 13

r = x i ri + x j r j

(13)

where xi and xj are the mole fractions of component i and j, respectively. The FH model can be extended to a ternary system to consider the water absorbed in a humid environment. (The corresponding FH equations for the ternary polymer/API/water system are summarized in Supplement 1 of the Supporting Information.) For that purpose, the interaction parameters between water and API χAPI,water and between water and polymer χpolymer,water were


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fitted to the same data as the PC-SAFT interaction parameters ki,water (Table 2) and are summarized in Table 3. For describing the interactions between the APIs and water in the FH model, a temperature dependent binary parameter (Eq 11) was introduced, as otherwise the modeling results did not fit the experimental data sufficiently well. This is in accordance with the PC-SAFT interaction parameters kAPI,water between naproxen or acetaminophen and water, which are also temperature dependent (Table 2). Table 3. FH interaction parameters between naproxen, acetaminophen, PVP K25 or PVPVA64, and water component i

χi,water

ARD (%)

data used for χi,water fitting

naproxen

1.23+122.11/T(K)

0.60

solubility of naproxen in water41

acetaminophen

0.74+128.51/T(K)

0.75

solubility of acetaminophen in water42

PVP K25

0.27

7.68

water sorption in PVP38

PVPVA64

0.77

3.76

water sorption in PVPVA38

Empirical model Another approach for calculating the solubility of an API in a polymer was developed by Kyeremateng et al.17.

TSL = −Aeb wAPI + T0SL,API + C

(14)

T SL is the solubility temperature for a certain API content w API (wt%) in the formulation. A and C are fitting parameters and b is set to -0.05 as shown in former work17. As Eq 14 is only suitable for two component systems, it cannot be used for predicting the impact in RH on the stability of ASDs.


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Calculation of glass-transition temperature A common equation for calculating the glass-transition temperature of a mixture is the Gordon-Taylor equation47.

∑K w T = ∑K w i

Tg

i

g ,i

(15)

i

i

i

i

The Gordon-Taylor equation (Eq 15) was used to calculate the glass-transition temperatures for ASDs in the absence and presence of water. Tg and Tg,i are the glass-transition temperatures of the ASD and the pure component i (API, polymer or water), respectively. wi is the amount (wt%) of component i in the formulation. The binary parameter Ki was calculated as follows

Ki =

ρ APITg,API

(16)

ρi Tg,i

from densities ρi and glass-transition temperatures Tg,i of the pure components, which are listed in Table 4. As no parameter was fitted to experimental data in Eqs 15 and 16, the calculation of the glass-transition temperature with the Gordon-Taylor equation is a full prediction. Table 4. Densities and glass-transition temperatures of naproxen, acetaminophen, PVP K25, PVPVA64 and water component i

naproxen

acetaminophen PVP K25

PVPVA64

water

ρ i (g/cm³)

1.2530

1.2948

1.2512

1.1949

150

Tg ,i (°C)

- 837

25 (this work)

16837

11137

-13850

MATERIALS AND METHODS Materials Naproxen and acetaminophen (polymorphic form I) were purchased from Sigma-Aldrich (Steinheim, Germany). The polymers PVP K25 (Kollidon 25) with an average molar mass of


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25 700 g/mol and PVPVA64 (Luvitec VA 64) with an average molar mass of 65 000 g/mol were purchased from BASF (Ludwigshafen, Germany).

Preparation of amorphous solid dispersions For long-term stability studies, ASDs of naproxen and acetaminophen with PVP K25 and PVPVA64 were prepared by hot-melt extrusion (HME) with the HAAKE MiniCTW microconical twin screw compounder from Thermo Fisher Scientific (Dreieich, Germany). The extrusion temperature was set to 150 – 170 °C and the rotation speed to 20 – 30 rpm. The compositions of the ASD samples are listed in Table 5. In all cases, the amount of polymer given in Table 5 was corrected for water content, which was measured by weight loss on drying method using Moisture Analyzer HB43-S from Mettler Todelo (Greifensee, Switzerland).


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Table 5. Composition of ASD samples for long-term stability studies and HME processing conditions used to manufacture them. API content (wt%)

system acetaminophen/PVP K25

acetaminophen/PVPVA64

naproxen/PVP K25

naproxen/PVPVA64

mAPI (g)

mpolymer (g)

30

6.1

14.9 a

41

8.3

12.7 a

50

10.0

10.6 a

11

2.2

19.0 b

20

4.0

16.9 b

31

6.2

14.7 b

40

8.0

12.6 b

52

11.2

10.7 b

60

12.2

8.4 b

25

5.0

16.0c

40

8.0

12.8c

50

10.0

10.7c

60

6.0

4.3c

5

1.0

19.8d

15

3.0

17.7 d

30

6.0

14.6 d

40

8.0

12.6 d

50

5.1

5.3 d

a

water content of 6.50 wt% in PVP K25 before extrusion, bwater content of 4.34 wt% in PVPVA64 before extrusion, cwater content of 6.55 wt% in PVP K25 before extrusion, d water content of 5.04 wt% in PVPVA64 before extrusion


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For measuring the solubility of acetaminophen in PVP K25 and the glass-transition temperature of the ASDs, samples with target API contents of 60 wt%, 70 wt% and 80 wt% were prepared by spray drying. The samples were prepared using a mini spray dryer B-290 with an inert-loop from Büchi (Essen, Germany). PVP K25 and acetaminophen were dissolved in 200 mL of ethanol with a total concentration of 10 g/L. The solution was fed to the spray dryer at a rate of 8 mL/min and an inlet temperature of 85 °C. Nitrogen was used as the drying gas at 601 L/h. The prepared samples were stored in vacuum at 25 °C for at least 48 hours to remove residual ethanol or moisture absorbed from the environment. Afterwards, the composition was investigated by UV/vis spectroscopy. For that purpose, 5 mg of the spray-dried sample was dissolved in 100 mL water and the acetaminophen concentration was measured by UV/vis spectroscopy. Five samples of each spray-dried ASD were measured and average values are reported. The samples prepared as described above turned out to have API contents of 60 (± 1) wt%, 70 (± 3) wt% and 85 (± 1) wt%. Due to the high API content of the spray-dried ASDs, they partially recrystallized into finelydispersed 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 API in the polymer by DSC.

Measuring API solubility in ASDs and glass-transition temperature of ASDs The solubility of acetaminophen in PVP K25 and the glass-transition temperatures of acetaminophen/PVP K25 ASDs were measured using a differential scanning calorimetry (DSC) apparatus Q2000 from TA Instruments (Eschborn, Germany). The measurement cell was purged


18

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with 50 mL/min of nitrogen. 5 – 10 mg of each spray-dried acetaminophen/PVP K25 sample was filled into a standard open aluminum pan to allow release of water, which was probably absorbed during sample preparation. Each sample was measured applying the following method: in a first step, the sample was heated from -10 °C to 170 °C with a heating rate of 2 K/min and kept isothermally at 170 °C for 5 minutes. In the next step, the sample was again cooled to -10 °C at 10 K/min and kept isothermally at -10 °C for 5 min before reheating at 10 K/min to 170 °C. The heating steps were conducted modulated with a modulation period of 60 s, and an amplitude of 0.318 K and 1.590 K for the first and second heating step, respectively. During the first heating step, water was removed and the acetaminophen crystals dissolved into the matrix, which led to an endothermic peak in the total heat flow. The offset of this peak was considered as the solubility temperature of the acetaminophen in the polymer. No recrystallization was observed during the cooling step. Thus, in the second heating step, the glass-transition temperature of the fully amorphous sample could be determined from the half height of the step in the signal of the reversing heat flow. Each sample was measured twice and the standard deviations of all solubility temperatures and glass-transition temperatures determined in this work were not higher than 1 K. The solubility temperature of the API in the polymer determined by DSC measurements usually linearly depends on the heating rate due to kinetic inhibition of dissolution16,18,51. For this reason, solubility temperature of each sample was additionally determined with heating rates of 1 K/min and 5 K/min with modulation period of 60 s and modulation amplitude of 0.159 K and 0.795 K, respectively. The equilibrium solubility temperature was determined by extrapolating the solubility temperatures measured at the different heating rates to a heating rate of 0 K/min. 16


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The solubility data of acetaminophen in PVPVA64 were taken from Kyeremateng et al.17, while the glass-transition temperature data were determined experimentally in this work. The solubility data and the glass-transition temperatures for the systems naproxen/PVP K25 and naproxen/PVPVA64 were taken from Prudic et al.37. In addition solubility data of naproxen in PVPVA64 from Kyeremateng et al.17 were considered.

Powder X-ray diffraction (PXRD) PXRD measurements were conducted using the bench top X-ray diffractometer MiniFlex 600 of Rigaku (Ettlingen, Germany). 25-50 mg of the milled sample were placed on a silicon sample holder and diffraction was measured with Cu-K alpha irradiation at a voltage of 40 kV and a current of 15 mA for angles between 2° and 45° with a speed of 5°/min and a step size of 0.02°. Defined peaks in the PXRD pattern indicate crystalline material in the sample. The location of these peaks equaled the patterns of pure crystalline naproxen or acetaminophen in its polymorphic form I. If the PXRD pattern shows only the amorphous halo without any characteristic crystalline peaks, it indicated that the ASD was fully amorphous.

Long-term stability studies Milled and unmilled ASD samples prepared by extrusion were stored at the following conditions: (1) 25 °C and dry, (2) 25 °C and 60% RH, (3) 40 °C and 75% RH. For condition (1) the milled and unmilled samples were stored in a vacuum chamber by Binder (Tuttlingen, Germany) and in a desiccator, respectively. The humid conditions (2) and (3) for the unmilled samples were achieved in climate rooms, where temperature and RH were adjusted with an accuracy of ± 2 °C and ± 5% RH, respectively. The milled samples were stored in a storage


20

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chamber by Binder (Tuttlingen, Germany) at 25 °C together with a saturated solution of sodium bromide in water, which ensures 60% (± 3%) RH (condition (2)), and in a WKL34 chamber by Weiss (Reiskirchen-Lindenstruth, Germany) set to 40 °C and 75% RH (condition (3)). After defined time intervals (½, 1, 2, 3, 4, 5, 6, 7, 9, 12, and 18 months) the milled samples were investigated for recrystallization by powder X-ray diffraction (PXRD). In addition, polarized-light microscopy (PLM) images with the Leica DMLM optical microscope equipped with a Leica DF320 digital camera (both from Leica Microsystems (Wetzlar, Germany)) were taken to confirm the results obtained by PXRD. The PLM imaging was performed using the unmilled samples. Measurements with UV/vis spectroscopy were performed for at least one sample per APIpolymer system stored at accelerated storage condition (40 °C/75% RH) to confirm that the API did not degrade during the stability studies.

RESULTS & DISCUSSION Modeling the phase behavior of water free ASDs The parameters for modeling the solubility of the APIs in the polymers were fitted to the experimental data of the API solubility in the polymers measured with DSC in this work or taken from Prudic et al.37 and Kyeremateng et al.17. The interaction parameters kAPI,polymer and χAPI,polymer for PC-SAFT and FH, respectively, were fitted as temperature independent values, which enabled correlating the API solubility in the polymers in good agreement with the experimental data. Moreover, parameters A and C for the empirical model (Eq 14) were fitted to the same data. The fitted parameters as well as the average relative deviation (ARD) of modeling and experimental data are summarized in Table 6 whereby the ARD was calculated using Eq 17.


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Page 22 of 52

n 1 exp w calc,i − w exp,i ARD = 100 ∑ w n exp i=1 exp,i

(17)

nexp is the number of experimental data points, wexp,i the measured API content (wt%) and wcalc,i the calculated API content at the same solubility temperature. The modeling results for the solubility of the APIs in the polymers obtained from the three models as well as the glasstransition temperatures predicted with the Gordon-Taylor equation together with the experimental data are shown in Figure 3. Table 6. Binary parameters for PC-SAFT, FH and the empirical model for modeling the solubility of acetaminophen or naproxen in PVP K25 or PVPVA64 System

PC-SAFT

FH

Empirical model

kAPI,polymer

ARD (%)

χAPI,polymer

ARD (%)

A

C

ARD (%)

acetaminophen/PVP K25

-0.0412

2.23

-1.33

3.81

471

3

5.65

acetaminophen/PVPVA64

-0.0563

0.69

-1.15

3.37

456

3

3.05

naproxen/PVP K25

-0.0782

0.56

-2.90

3.13

652

4

0.63

naproxen/PVPVA64

-0.0574

2.05

-2.36

2.09

552

4

1.97


22

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Figure 3. Phase behavior of ASDs. (a) acetaminophen/PVP K25, (b) acetaminophen/PVPVA64, (c) naproxen/PVP K25, and (d) naproxen/PVPVA64. The triangles show the solubility of the APIs in the polymers experimentally determined in this work for (a) or taken from Literature for (b)-(d), where white triangles were taken from Kyeremateng et al.17 and black triangles from Prudic et al.37. The green squares are experimental data of the glass-transition temperature determined in this work for (a) and (b) and from literature for (c) and (d)37. The curves show modeling results for the API solubility calculated with PC-SAFT (orange), FH (black) and the empirical model (blue). The green curves (green) show the glass-transition temperature predicted using the Gordon-Taylor equation. As can be seen, the experimental data for the solubility of the APIs in the polymers can be satisfactorily correlated using the three models, PC-SAFT, FH and the empirical model (Figure 3). The ARDs are smaller than 6% for all investigated systems and models, as listed in Table 6. However, experimental solubility data are only accessible at high temperature. As all three


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Page 24 of 52

models well correlate these experimental data, it becomes even more important to evaluate the accuracy of the models at storage temperature, i.e. room temperature. Indeed, at lower temperatures the modeling results obtained from the three different models deviate from each other. In general, the FH model calculates a lower API solubility at low temperatures than PCSAFT or the empirical model. The difference between the results of PC-SAFT and FH can be explained with the interactions considered by the two models. The FH model was initially developed for polymer solutions based on the assumption that polymer segments and solvent molecules are statistically distributed in a lattice52. The interaction parameter χij accounts for attractive (χij < 0) or repulsive forces (χij > 0)20,53 , but does not differentiate between the different interaction types. In contrast, PC-SAFT considers different contributions for interactions, such as dispersion and association. The association term accounts for hydrogen bonding between the components, API and polymer, which is temperature dependent36,54. While the FH model does not include the temperature dependent association, the calculation with PC-SAFT considers the strength of the hydrogen bonds, which increases with decreasing temperature. For that reason PC-SAFT leads to a higher solubility of the APIs in the polymers at low temperatures than FH. The empirical model does not consider any specific interactions, but for the systems acetaminophen/PVPVA64 and naproxen/PVP K25 it is close to the results calculated with PCSAFT. For acetaminophen/PVP K25, it predicts a higher solubility than FH and a lower solubility than PC-SAFT, while for naproxen/PVPVA64 it predicts the highest solubility among the three models. However, as the empirical approach was developed based on fitting of a large data set of measured solubilities of APIs in polymers, the parameters A and C in the model do


24

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not have a physical meaning17. For that reason, similarities or deviations from the other two models cannot be explained on a physical basis. The glass-transition temperatures predicted with the Gordon-Taylor equation are in good agreement with the experimental data for the systems with naproxen. The ARDs (Eq 17) are 0.78% for naproxen/PVP K25 and 1.24% for naproxen/PVPVA6437. For the ASDs with acetaminophen the prediction with Gordon-Taylor leads to higher glass-transition temperatures than experimentally determined. The ARDs are 24.73% for acetaminophen/PVP K25 and 22.24% for acetaminophen/PVPVA64. These deviations allow to draw conclusions on the strength of the intermolecular interactions48. The negative deviation of measured glass-transition temperatures of the acetaminophen/polymer systems from Gordon-Taylor predictions indicates that the interactions between acetaminophen and the polymers are weaker than the interactions between molecules of the same type (API/API and polymer/polymer)48. In contrast, the agreement of measured glass-transition temperatures in the

naproxen/polymer

systems

and

the

Gordon-Taylor

predicitions

reveals

that

naproxen/polymer interactions are of a similar strength than naproxen/naproxen and polymer/polymer interactions. Hence, acetaminophen binds weaker to the polymers than naproxen. This also corresponds to the fact that the binary FH and PC-SAFT parameters are less negative for the acetaminophen ASDs than for the naproxen ASDs (Table 6), which as well indicates weaker acetaminophen/polymer interactions compared to naproxen/polymer24,31. Nevertheless, it can be concluded that the Gordon-Taylor equation is suitable to qualitatively predict the glass-transition temperature, and thus, the kinetically stabilized area of the phase diagram.


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Long-term stability of dry ASDs As no experimental data of the APIs solubility in polymers are accessible at room temperature, long-term stability studies were carried out to validate the model predictions at these temperatures. The extruded ASDs were stored in a vacuum oven or desiccator at 25 °C to eliminate the influence of moisture. Before storage, none of the samples showed PXRD patterns characteristic of the crystalline peaks. Furthermore, no crystals were observed in the PLM images, indicating that the samples were fully amorphous before storage. All samples were investigated for recrystallization by PXRD and PLM imaging periodically. The results of the long-term studies after 18 months are presented in Figure 4 alongside their respective modeled phase diagrams already shown in Figure 3.


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Figure 4. Stability studies of dry ASDs at 25 °C. (a) acetaminophen/PVP K25, (b) acetaminophen/PVPVA64, (c) naproxen/PVP K25 and (d) naproxen/PVPVA64. The circles and stars reflect amorphous and recrystallized samples, respectively. The numbers on the symbols indicate the period in months, after which recrystallization was observed by PLM or PXRD or full amorphous state was still maintained. The curves show modeling results calculated with PCSAFT (orange), FH (black), and the empirical model (blue). The green curves show the glasstransition temperature predicted using the Gordon-Taylor equation. As shown in Figure 4, some samples, notably in the high API content region, recrystallized after one to 18 months. As expected, all recrystallized samples have API contents significantly higher than the solubility predicted by the three models at 25 °C. As already indicated, ASDs in this region are not thermodynamically stable but only kinetically stabilized, and therefore susceptible to recrystallize.


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Besides other API physicochemical properties55 the rate of recrystallization of a supersaturated ASD mainly depends on two factors; the extent of supersaturation relative the thermodynamic equilibrium solubility (how far right the API content is from the solubility curve) and molecular mobility. The molecular mobility largely depends on the glass-transition temperature of the ASD, and the higher the difference between the storage temperature and the glass transition temperature the slower the molecular mobility12–14,56. With increasing API content above the solubility limit, the degree of supersaturation increases while the glass-transition temperature of the ASD decreases for all systems. Recrystallization should therefore occur earlier for supersaturated samples with higher API content and lower glass-transition temperature as seen in Figure 4. For instance, all PVPVA64-based samples (Figures 4b and d) predicted to be kinetically stabilized and far to the right of the modeled solubility line (by at least one of the models) recrystallized within 18 months at room temperature and dry condition. Contrarily, naproxen/PVP and acetaminophen/PVP samples with approximately 40 wt% API content, which are far to the right of the solubility lines calculated with all three models and predicted to be kinetically stabilized, did not recrystallize within 18 months (Figures 4a and c). According to Zografi and coworkers12, kinetically-stabilized amorphous material needs to be stored at least 50 °C below the glass-transition temperature to achieve long-term physical stability. This rule seems to hold true for most of the ASDs presented in Figure 4. As seen in Figure 4, mainly samples with high API content, where the difference between the storage temperature (25 °C) and the glass-transition temperature is smaller than 50 °C, i.e. only samples with glass-transition temperatures below 75 °C recrystallized within the 18 months period.


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Only the sample with 30 wt% naproxen in PVPVA64, which is supersaturated but close to the predicted solubility lines deviates from this rule: the sample is still amorphous after 18 months, although it is stored less than 50 °C below glass-transition temperature (Tg = 67 °C). Obviously, a deviation from the stated rule can occur if the sample composition is close to the API solubility line and thus the driving force for recrystallization is very small. Nevertheless, the finding of Zografi and coworkers12 is useful for roughly estimating the composition range of kinetic stabilization.

Modeling the influence of RH on the phase behavior of ASDs PC-SAFT and FH were extended for ternary systems to consider also water besides the API and the polymer in the ASD. The empirical model was developed for two-component systems only and therefore cannot be used for predicting the impact of RH. Based on binary interactions between API and water, polymer and water, as well as polymer and API, the phase behavior of the ASDs was predicted for 60% RH and 75% RH using PC-SAFT and FH. The interaction parameters between APIs and polymers, kAPI,polymer for PC-SAFT, and χAPI,polymer for FH, had already been fitted for modeling the phase behavior of the dry ASDs and can be found in Table 6. The PC-SAFT and FH interaction parameters between the ASD components (API and polymer) and water ki,water and χi,water are listed in Table 2 and Table 3, respectively. The influence of RH on the phase behavior predicted by PC-SAFT and FH is shown in Figure 5 for acetaminophen/PVP K25 and naproxen/PVP K25. The glass-transition temperature was predicted using the ternary Gordon-Taylor equation (Eq 15), after the water content was calculated with PC-SAFT.


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Figure 5. Influence of RH on the phase behavior of ASDs. (a) acetaminophen/PVP K25 and (b) naproxen/PVP K25. The orange curves show the solubility of the APIs in PVP K25 calculated with PC-SAFT and the black curves show the solubility calculated with FH. The green curves show the glass-transition temperatures calculated using the Gordon-Taylor equation. Full, dashed and dotted lines reflect 0%, 60% and 75% RH, respectively. The x-axis refers to the API content relative to only the polymer. For both systems presented in Figure 5, the calculated glass-transition temperature significantly decreased with increasing RH. This effect increases with decreasing API content. The polymers, PVP K25 and PVPVA64, are highly hygroscopic in contrast to the APIs, naproxen and acetaminophen. For that reason the water uptake increases with decreasing API content. Water has a very low glass-transition temperature of -138 °C50, and the more water is absorbed, the more the glass-transition temperature of the ASD is decreased. The FH model predicts a slight increase of the acetaminophen solubility at the storage temperatures (25 °C and 40 °C) with increasing RH (Figure 5a). The difference between the solubility of acetaminophen in PVP K25 at 25 °C/60% RH and the solubility at 25 °C/0% RH is + 3 wt% (g/g). At 40 °C/75% RH the solubility increases by even + 6 wt% compared to the dry


30

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storage. The impact of RH on the acetaminophen solubility predicted by PC-SAFT for storage conditions is smaller (+ 1 wt% for 25 °C/60% RH and + 2 wt% for 40 °C/75% RH). Overall, PCSAFT predicts that approximately 32 wt% and 35 wt% of acetaminophen is soluble in PVP K25 at 25 °C/60% RH and 40 °C/75% RH, respectively, whereas the FH model predicts 12 wt% and 18 wt% for the same conditions. In contrast, the predictions with both PC-SAFT and FH model show a significant decrease of the naproxen solubility in PVP K25 with increasing RH (Figure 5b). The decrease effect predicted with PC-SAFT is stronger, such that naproxen solubility predicted for 40 °C/75% RH is 5.8 wt%, which is close to the prediction with FH (6.7 wt%), although at dry conditions the predictions differ remarkably from each other (34 wt% with PC-SAFT compared to 20 wt% with FH). The different impact of RH on the solubility of the two APIs, acetaminophen and naproxen, in PVP K25 is caused by the difference in their hydrophilicity. Acetaminophen is a highly watersoluble API with a solubility of 14.9 g/kgwater at 25 °C42, while naproxen is a poorly watersoluble API (0.029 g/kgwater at 25 °C41). For this reason, water uptake slightly increases the solubility of acetaminophen in the polymer matrix, but decreases that of naproxen. The same trends of the API solubility dependence on RH were predicted for the PVPVA64 systems. The solubility of acetaminophen in PVPVA64 increases with increasing RH, while the solubility of naproxen decreases.

Long-term stability of ASDs exposed to humidity To validate the prediction of the phase behavior under humid conditions, long-term stability studies were conducted at 25 °C/60% RH as well as at 40 °C/75% RH. The results for the ASDs


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Page 32 of 52

of acetaminophen/PVP K25 and acetaminophen/PVPVA64 are presented in Figure 6. Corresponding experimental data of the water sorption compared to the predictions with PCSAFT and FH can be found in Supplement 2 of the Supporting Information.

Figure 6. Stability studies of acetaminophen ASDs exposed to humidity. (a) acetaminophen/PVP K25 at 25 °C/60% RH , (b) acetaminophen/PVP K25 at 40 °C/75% RH, (c) acetaminophen/PVPVA64 at 25 °C/60% RH, and (d) acetaminophen/PVPVA64 at 40 °C/75% RH. The circles and stars reflect amorphous and recrystallized samples, respectively. The numbers on the symbols indicate the period in months, after which recrystallization was observed by PLM or PXRD or full amorphous state was still maintained. The curves show modeling results calculated with PC-SAFT (orange) and FH (black). The green curves show the glass-transition temperature predicted using the Gordon-Taylor equation. The x-axis refers to acetaminophen content relative to only the polymer.


32

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As described before and shown in Figure 6, the glass-transition temperature decreases with increasing RH, so that at 75% RH the glass-transition temperature for all systems is reduced to the extent that the storage temperature of 40 °C is higher than the glass-transition curve. Meaning, all the samples stored at 40 °C/75% RH are stored above the glass-transition temperature, and therefore, kinetic stabilization via glassy state is non-existing for all the samples under this condition. At 60% RH the samples are stored at 25 °C, which is slightly below the glass-transition curve, indicating that kinetic stabilization is very low under this storage condition. As expected, the kinetically-stabilized 41 wt% acetaminophen/PVP K25 ASDs which did not recrystallize after 18 months storage at 25 °C/0% RH now recrystallized within 7 months, upon storage at 25 °C/60% RH as shown in Figure 6a.. When stored at 40 °C/75%RH (Figure 6b), the 41 wt% acetaminophen/PVP K25 ASD recrystallized even faster within 4 months as kinetic stabilization via glassy state is very low under this condition. The 30 wt% acetaminophen/PVP K25 ASD, however, remained amorphous under both of the humid conditions for 18 months. According to the PC-SAFT model, the 30 wt% acetaminophen/PVP K25 ASD is undersaturated and thermodynamically stable under these conditions, which means that crystallization should not occur even after infinite time. In contrast, the FH model predicts that this formulation is supersaturated under the humid conditions, hence, thermodynamically unstable and should crystallize when kinetic stability via glassy state is very low. These stability results indicate that the PC-SAFT model predicts the solubility of acetaminophen in the PVP more accurately than the FH model. The same conclusions can be drawn for the acetaminophen/PVPVA64 ASD systems shown in Figure 6c and 6d, and supported by the PLM images shown in Figure 7 for 25 °C/60% RH as


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Page 34 of 52

well as PXRD diffractograms for 40 °C/75% RH shown in Figure 8. As seen in Figure 7, the sample with 31 wt% acetaminophen remained amorphous after 12 months, while the samples with 40 wt% and with 52 wt% API recrystallized within 4 months and 2 weeks, respectively.

Figure 7: PLM images of acetaminophen/PVPVA64 extrudates stored at 25 °C/60% RH. (a) 31 wt% acetaminophen, after 12 months, (b) 40 wt% acetaminophen, after 4 months, and (c) 52 wt% acetaminophen , after 2 weeks. Images (b) and (c) show birefringence in the exrudates due to recrystallized acetaminophen, whereas image (a) shows a completely amorphous extrudate.

The PXRD diffractograms of acetaminophen/PVPVA64-samples stored at 40 °C/75% RH for twelve months (Figure 8) with 52 wt% and 60 wt% API show very pronounced characteristic peaks corresponding to crystalline acetaminophen. In contrast, the peaks in the diffractogram of the 40 wt% sample are small and nearly inconspicuous. Thus, this sample is PXRD crystalline and therefore supersaturated, however, the very low intensity of the peaks also suggests that the crystalline content is very low. API crystal growth is possible as long as the residual amorphous part of the sample is supersaturated and it stagnates as soon as the concentration in the amorphous phase reaches the solubility of the API in the polymer. The fact that the sample was stored above the glasstransition temperature and crystals were first observed after 0.5 months but their content is still small after 12 months, suggests that the API thermodynamic solubility at this condition is only slightly below 40 wt%. Hence, samples with 11 wt%, 20 wt%, and 31 wt% API (being below the


34

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solubility limit) were PXRD amorphous after 18 months at the accelerated storage condition (40 °C/75% RH). In effect, the PXRD-diffractograms in Figure 8 validate the position of the PCSAFT-predicted solubility curve for the acetaminophen/PVPVA64-system at 40 °C/75% RH (Figure 6d).

Figure 8: PXRD-diffractograms of pure crystalline acetaminophen (form I) and pure amorphous PVPVA64 and acetaminophen/PVPVA64-samples with different API contents stored at 40 °C/75% RH for 12 months.

In summary, FH seems to underestimate the solubility of acetaminophen in both polymers, while PC-SAFT is in good agreement with the results of the long-term stability studies of the acetaminophen ASDs. The

results

of

the

long-term

stability

studies

for

the

naproxen/PVP K25

and

naproxen/PVPVA64 ASDs are presented in Figure 9. Corresponding experimental data of the


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Page 36 of 52

water sorption compared to the predictions with PC-SAFT and FH can be found in Supplement 2 of the Supporting Information. +

Figure 9. Stability studies of naproxen ASDs exposed to humidity. (a) naproxen/PVP K25 at 25 °C/60% RH, (b) naproxen/PVP K25 at 40 °C/75% RH, (c) naproxen/PVPVA64 at 25 °C/60% RH, and (d) naproxen/PVPVA64 at 40 °C/75% RH. The circles and stars reflect amorphous and recrystallized samples, respectively. The numbers on the symbols indicate the period in months, after which recrystallization was observed by PLM or PXRD or full amorphous state was still maintained. The curves show modeling results calculated with PCSAFT (orange) and FH (black). The green curves show the glass-transition temperature predicted using the Gordon-Taylor equation. The x-axis refers to the naproxen content relative to only the polymer.


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Unlike the acetaminophen ASDs, the solubility predictions with PC-SAFT and FH model for the naproxen ASDs at the humid conditions are close to each other (in the temperature region of interest, 25 °C – 40 °C) except for the naproxen/PVP K25 system at 25 °C/60% RH. While PCSAFT predicts 24 wt% API solubility for the system at this condition, the FH model predicts 10 wt% API solubility for the same condition. Generally, all naproxen ASDs predicted to be supersaturated by either PC-SAFT or the FH model recrystallized with the period of the studies. However, ASD samples with API contents less, equal or very close to the predicted solubility by the models still remained amorphous after 18 months. As expected, the least-kinetically stabilized (low Tg) and supersaturated samples which were far from the predicted equilibrium solubility recrystallized already within short periods of 0.5 to 1 month. This applies to naproxen/PVP K25 samples with API content higher than 40 wt% and to naproxen/PVPVA64 samples with API content higher than 30 wt% at 25 °C/60% RH. The other kinetically-stabilized samples with higher glass-transition temperatures took longer periods to recrystallize under this condition. With the exception of 25 wt% naproxen/PVP K25, all the samples predicted to be supersaturated by both models recrystallized even faster (within 0.5 months) when RH was increased to 75% where non of the samples were kinetically stabilized via glassy state (Figure 9b and d). Although predicted to be well supersaturated by both models andnon-kinetically stabilized via glassy state, the 25 wt% naproxen/PVP K25 sample exceptionally did not recrystallize within short period under this condition (Figure 9b). Nevertheless, first crystals could be observed only after twelve months, which was confirmed with the PXRD diffractograms and PLM images in Figure 10. As seen in Figure 10, even nine months after


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storage, the PXRD diffractogram did not show naproxen-characteristic peaks, which is also confirmed by the non-birefringent PLM image of the sample. However, after twelve months characteristic naproxen peaks were found by PXRD and birefringent crystal seeds could be observed in the corresponding PLM image. These observations potentially point toslow nucleation and recrystallization kinetics of this supersaturated ASD, even for a storage temperature significantly higher than the glass-transition temperature. A plausible reason for the extreme slow recrystallization kinetics is the strong specific interactions between naproxen and PVP. Similar to other carboxylic acid bearing APIs such as indomethacin and ibuprofen, naproxen forms strong hydrogen bonding between its carboxylic acid hydrogen (-COOH) and the amide carbonyl (C=O) of the polymers13,17,30,57. This strong specific interaction is reflected in the very negative FH χAPI,polymer values, which is indicating stronger attractive interactions between naproxen the polymers compared to acetaminophen24. Also for PC-SAFT, naproxen/PVP K25 has the most negative kAPI,polymer value of the investigated systems (Table 6). According to Eq 4 a low kij value corrects the dispersion energy uij in a mixture to a higher value, which indicates strong attraction forces between naproxen and PVP K25. Several spectroscopic techniques studies including FT-IR and dielectric suggest that strong API-polymer interactions, by reducing mobility, can potentially delay recrystallization of an API from the ASD58-60. Moreover, solid state NMR and FT-IR spectroscopic investigations by Munson and coworkers61, and Kyeremateng et al.17, respectively, revealed that at low API contents (high polymer contents) all the carboxylic acid hydrogen of such acidic APIs are H-bonded to the amide carbonyl of the polymer in the ASD. Since naproxen forms a crystal lattice based on a catamer hydrogen bonding between its carboxylic groups, the ability of the polymer to H-bond with all the carboxylic groups of naproxen at low API contents


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can effectively prevent the crystallization62. Therefore, the extremely slow or delayed recrystallization of the supersaturated 25 wt% naproxen/PVP K25 ASD stored at 40 °C/75 % RH can be attributed to the strong H-bonding existing between the API and the polymer. It also infers that validating precisely both PC-SAFT and FH models for the naproxen ASDs at low API contents is challenging as the recrystallization is extremely slow and could probably take several years of stability studies, which is out of scope of this work, to identify which model’s prediction is more accurate.

Figure 10: PXRD spectra (left) and PLM images (right) of naproxen/PVP K25 with 25 wt% naproxen after nine and twelve months at 40 °C/75% RH.

CONCLUSION The aim of this work was the investigation of ASD physical stability based on both, experiments and thermodynamic modeling of the phase diagrams. For the latter, three different models were applied for the calculation of the API solubility in polymers and compared towards


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their ability to model the experimental data. For that purpose, ASDs of the APIs, naproxen and acetaminophen, and the excipient polymers, PVP K25 and PVPVA64, were investigated. The solubility of APIs in dry polymers accessible by DSC measurements at high temperatures was extrapolated with PC-SAFT, the Flory-Huggins (FH) model and an empirical model to the storage temperatures. The glass-transition temperature, which is related to the kinetic stability, was calculated with the Gordon-Taylor equation. Furthermore, the impact of RH was investigated by using PC-SAFT, the FH model and the Gordon-Taylor equation for a ternary API/polymer/water-system. Long-term stability studies at standardized storage conditions, 25 °C/0% RH, 25 °C/60% RH, and 40 °C/75% RH were conducted and the results were compared to the predictions by the different models. It could be shown that at dry conditions the calculations with PC-SAFT, FH and the empirical model were in good agreement to the DSC measurements. At room temperature (25 °C) and 0% RH the FH model generally predicts a lower solubility of acetaminophen and naproxen in PVP K25 and PVPVA64 than PC-SAFT and the empirical model. The glass-transition temperature of the dry ASD formulations was quite high, so that most samples at 25 °C/0% RH were stored more than 50 °C below the glass-transition temperature. At these conditions the samples are strongly stabilized kinetically due to glassy state, so that recrystallization of the supersaturated ASDs was not expected, at least within the time frame of this study, as confirmed by the results of the long-term stability studies. PC-SAFT and FH both predict a small influence of RH on the acetaminophen solubility in the polymers, while the naproxen solubility is significantly decreased with increasing RH. At humid conditions recrystallization is highly accelerated, because the glass-transition temperature is strongly decreased.


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The stability studies with the acetaminophen/PVP K25- and acetaminophen/PVPVA64systems at 25 °C/60% RH and 40 °C/75% RH lead to the conclusion, that the FH model underestimates the solubility of acetaminophen in the two polymers, while the prediction with PC-SAFT separates very well stable amorphous from unstable recrystallized samples in accordance with the experimental findings. For the systems naproxen/PVP K25 and naproxen/PVPVA64, the predictions of PC-SAFT and FH at 25 °C/60% RH and 40 °C/75% RH are very similar. All samples, which were predicted to be supersaturated by the two models, recrystallized during the 18 months study. The comparison of long-term stability studies with the predicted phase diagrams shows that thermodynamic models are suitable tools to extrapolate experimental data of the API solubility in dry polymers and at high temperatures to conditions, which are relevant for the storage of ASDs but inaccessible by DSC measurements. Especially PC-SAFT showed a high predictive power as it could be used for predicting the impact of RH on the ASD phase behavior and agreed with the results of the 18 months-long stability studies of the four API/polymer systems and all storage conditions investigated within this work.


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ASSOCIATED CONTENT Supporting Information Ternary Flory-Huggins equations for predicting the influence of RH on the phase behavior of ASDs. Measurement and calculation of water sorption in dependence of 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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+49-231-755-2635;

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dortmund.de Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. 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. Samuel Kyeremateng, Oliver Heinzerling, Matthias Degenhardt and Kristin Lehmkemper are AbbVie employees and may own AbbVie stock/options. Gabriele Sadowski is


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an employee at the Department for Biochemical and Chemical Engineering of the Technical University of Dortmund and has no conflict of interest to report. ACKNOWLEDGMENT The authors would like to thank David Gessner of AbbVie Deutschland GmbH & Co. KG, Ludwigshafen for his assistance with PLM imaging and Stefanie Dick and Hoang Tam Joseph Do, students at the Department of Biochemical and Chemical Engineering (TU Dortmund), for conducting PXRD measurements. ABBREVIATIONS a, Helmholtz energy (J); A, C, fitting parameters in empirical model; b, constant in empirical SL

model; ∆cp,0,API , difference in the solid and liquid heat capacities of the pure API (J/molK);

∆h SL 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; NAV, Avogadro number; p, pressure (Pa); R, universal gas constant (8.1345 J mol-1 K-1); rij, segment number of component j; SL

T, temperature (K); T0,API, melting temperature of the pure API (K), Tg, glass-transition temperature (K); u/kB dispersion-energy parameter; v, molar volume; w, content (wt%); x, mole fraction; Z, compressibility factor; γ, activity coefficient; εAiBi/kB association-energy parameter, κAiBi, association-volume parameter; µ, chemical potential; φ, fugacity coefficient; ρ, density (g/cm³); σ, segment diameter; χij, FH binary interaction parameter 0, pure component; Ai, Bi, association sites A and B of molecule i; API, active pharmaceutical ingredient; assoc, association; calc, calculated; disp, dispersion; exp, experimental; hc, hard


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chain; i, j, component indices; L, liquid phase; LV, liquid-vapor; res, residual; S, solid phase; seg, segment; SL, solid-liquid; V, vapor; API, active pharmaceutical ingredient; ARD, average relative deviation; ASD, amorphous solid dispersion; DSC, differential scanning calorimetry; FH, Flory-Huggins model; HME, hot melt extrusion; PC-SAFT, Perturbed-Chain Statistical Associating Fluid Theory; PLM, polarized light microscope; PVP K25, poly(vinyl pyrrolidone) (Kollidon 25); PVPVA64, poly(vinyl pyrrolidone-co-vinyl acetate) (VA64); PXRD, powder X-ray diffraction; RH, relative humidity; SLE, solid-liquid equilibrium; VSLE, vapor-solid-liquid equilibrium REFERENCES (1) Babu, N. J.; Nangia, A. Solubility advantage of amorphous drugs and pharmaceutical cocrystals. Cryst. Growth Des. 2011, 11, 2662–2679. (2) Di, L.; Fish, P. V.; Mano, T. Bridging solubility between drug discovery and development. Drug Discovery Today. 2012, 17, 486–495. (3) Grohganz, H.; Priemel, P. A.; Löbmann, K.; Nielsen, L. H.; Laitinen, R.; Mullertz, A.; van den Mooter, G.; Rades, T. Refining stability and dissolution rate of amorphous drug formulations. Expert Opin. Drug Deliv. 2014, 11, 977–989. (4) Leuner, C. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm. 2000, 50, 47–60. (5) 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. (6) Huang, Y.; Dai, W.-G. Fundamental aspects of solid dispersion technology for poorly soluble drugs. Acta Pharm. Sin. B. 2014, 4, 18–25.


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For Table of Contents Use Only Title: Long-term physical stability of PVP- and PVPVA-amorphous solid dispersions Authors: Kristin Lehmkemper, Samuel O. Kyeremateng, Oliver Heinzerling, Matthias Degenhardt, Gabriele Sadowski


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Long-Term Physical Stability of PVP- and PVPVA ... - ACS Publications

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