Use of a Plasticizer for Physical Stability Prediction of Amorphous

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The use of a plasticizer for physical stability prediction of amorphous solid dispersions Michelle H. Fung, and Raj Suryanarayanan Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b00625 • Publication Date (Web): 23 Jun 2017 Downloaded from http://pubs.acs.org on June 26, 2017

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Crystal Growth & Design

Figure 1. Effect of glycerol concentration on the glass transition temperatures of (a) amorphous celecoxib (COX), ketoconazole (KTZ), and (b) PVP-KTZ and PVP-COX ASDs. 177x66mm (300 x 300 DPI)

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Figure 2. FTIR spectra of (a) PVP-COX physical mixture and ASD and (b) PVP-COX ASDs with different glycerol concentrations. 177x66mm (300 x 300 DPI)


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Figure 3. Dielectric loss spectra (permittivity vs. frequency) of (a) amorphous KTZ, (b) amorphous COX, (c) PVP-KTZ ASDs and (d) PVP-COX ASDs with different glycerol concentrations. 177x132mm (300 x 300 DPI)



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Figure 4. Temperature dependence of α-relaxation times of (a) amorphous KTZ, (b) amorphous COX, (c) PVP-KTZ ASDs and (d) PVP-COX ASDs with and without glycerol obtained using DES. 177x132mm (300 x 300 DPI)


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Figure 5. Plots of τα as a function of temperature, scaled for dielectric Tg. (a) amorphous KTZ, (b) amorphous COX, (c) PVP-KTZ ASDs and (d) PVP-COX ASDs. Each system was plasticized with glycerol (up to 2% w/w). 177x132mm (300 x 300 DPI)



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Figure 6. DSC heating curves of (a) amorphous KTZ, (b) amorphous COX, (c) PVP-KTZ ASDs, and (d) PVPCOX ASDs. 177x132mm (300 x 300 DPI)


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Figure 7. One dimensional XRD patterns obtained from the 2D synchrotron XRD images. (a) PVP-KTZ and (b) PVP-COX ASDs, after storage at 45℃ for 14 days and at 75℃ for 96 hours for the two drug systems respectively. 177x66mm (300 x 300 DPI)



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Figure 8. A plot of time for 10% crystallization vs. α-relaxation time of PVP-COX ASDs with 0 to 2% w/w glycerol. 177x53mm (300 x 300 DPI)


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The use of a plasticizer for physical stability prediction of amorphous solid dispersions Michelle H. Fung1, Raj Suryanarayanan1* 1

Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota

55455, USA *Corresponding Author: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, United States. Phone: 612-624-9626. Fax: 612-6262125. E-mail: [email protected]

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ABSTRACT Utilizing glycerol as a plasticizer, an accelerated physical stability testing method of amorphous solid dispersions (ASD) was developed.

The influence of glycerol

concentration on the glass transition temperature and α-relaxation time (a measure of molecular mobility) of amorphous ketoconazole, celecoxib and the solid dispersions of each prepared with polyvinyl pyrrolidone was investigated.

By temperature scaling

(Tg/T), the effects of glycerol concentration and temperature on the relaxation time were simultaneously evaluated. Glycerol, in a concentration dependent manner, accelerated crystallization in all of the systems without affecting the fragility.

In celecoxib-PVP

ASDs, the drug crystallization was well coupled to molecular mobility and was essentially unaltered at glycerol concentrations up to 2% w/w.

The acceleration in

crystallization brought about by glycerol expedited the determination of the coupling between molecular mobility and crystallization. As a result, we were able to predict the physical stability of the unplasticized ASD. This approach is especially useful for ASDs with high polymer content where drug crystallization is extremely slow at relevant storage temperature. Keywords: celecoxib, ketoconazole, amorphous solid dispersions, plasticizer, molecular mobility, crystallization, dielectric spectroscopy


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INTRODUCTION Amorphous solid dispersion (ASD) is a popular formulation strategy for improving the oral bioavailability of poorly water soluble APIs1-3.

However, recrystallization of

amorphous API during storage or dissolution would eliminate the solubility advantage of amorphous pharmaceuticals and lead to product failure. Accelerated studies conducted under elevated temperature and water vapor pressure cannot be reliable predictors of stability under relevant storage conditions. The goal of this study was to develop an “accelerated method” to evaluate the physical stability of drugs in ASDs. In these systems, molecular mobility provides an avenue to assess physical stability. While there are several tools to evaluate mobility, a unique advantage of dynamic dielectric spectroscopy (DES) is that it can simultaneously characterize different modes of molecular motions, over a wide temperature range. More importantly, the potential coupling between mobility and physical stability provides an avenue to predict crystallization behavior from mobility measurements. The coupling between mobility and crystallization was built on the idea that drug crystallization rate at a crystal-melt interface, G(T), can be estimated from the temperature

dependence

of

translational

molecular

diffusion,

D(T),

and

the

thermodynamic driving force for nucleation, f(T) 4. () = () ∙ () (Equation 1) Since it can be difficult to measure translational molecular diffusion, D(T) is often approximated by the temperature dependence of the viscosity, () resulting in Equation 2. ( )

() = ( )

(Equation 2)

Furthermore, due to the similar temperature dependence of and the rotational motions measured by DES, crystallization rate, G(T), can be approximated by the following expression, ( )

() ∝

( )

(Equation 3) 3



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where () is the temperature dependence of α-relaxation time measured by DES. However the Stokes-Einstein equation, relating translational diffusion to viscosity, breaks down over the temperature range of Tg to 1.2 Tg5. The decoupling between translational diffusion and viscosity can be expressed as follows:

() ∝ ( ) (Equation 4) where is the decoupling factor. The relationship between crystallization and relaxation times can be described by: () ∝

( )

( )

(Equation 5)

where M is the coupling coefficient and indicates the coupling between crystallization and molecule mobility. Equation 5, when represented in terms of crystallization time, , yields Equation 6. () ∝

( ) ( )

(Equation 6)

Over a narrow temperature range (~20 ̊ C), the relationship between crystallization time ( ) and molecular mobility ( ) can be expressed by Equation 7, providing an avenue to obtain the coupling coefficient (M). log = log + (Equation 7) In this equation, A is a constant related to the thermodynamic driving force of crystallization, f(T).

An M value of 1 indicates perfect coupling between molecular

mobility and crystallization. There are different ways of representing the crystallization time (tc) - onset time for crystallization (t0), time for the desired fraction of drug crystallization (for example, t2.5%, t5% and t10% representing respectively time for 2.5, 5 and 10% drug crystallization). In amorphous itraconazole, Bhardwaj et al showed that the α-relaxation time was strongly coupled to crystallization onset time, with a coupling coefficient of 0.946. Kothari et al observed that an increase in polyvinyl pyrrolidone (PVP) concentration 4 ACS Paragon Plus Environment

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from 2.5 to 10% w/w caused a pronounced reduction in molecular mobility while the coupling coefficient value (between mobility and time for 10% nifedipine crystallization) was essentially unaltered (~ 0.7)7. More recently, ASDs were prepared with polymers which differed widely in the strength of their interaction with the model drug, ketoconazole8-9. The coupling coefficient appeared to be independent of the strength of drug-polymer interactions. The physical stability of amorphous pharmaceuticals is known to be sensitive to the sorbed water content, an effect attributed to the plasticizing effect of water. We had earlier investigated the influence of sorbed water content on the molecular mobility of ASDs10-15. Since both molecular mobility and drug crystallization exhibited a similar magnitude of increase due to water sorption, the coupling coefficients of the waterplasticized and the dry dispersions were about the same. While water can accelerate drug crystallization through plasticization, there are potential drawbacks with its use. The high dielectric constant of water causes a pronounced conductivity response in the low frequency region of the DES spectra16.

This can

potentially interfere with the characterization of α-relaxation. While glycerol with a Tg of 190 K, is similar to water in its ability to cause pronounced plasticization, its dielectric constant (42.5) is approximately half that of water17,18. Consequently, the interference attributable to dc-conductivity in the DES spectra would be much less pronounced than that due to water. A second practical disadvantage with water is its high vapor pressure in the experimental temperature range.

As a result, there is potential for water

vaporization during the experiment leading to erroneous results. This problem is much less encountered with glycerol, which has a substantially higher boiling point (290 °C). The overall goal of our work is to develop an accelerated stability testing method to predict the physical stability of ASDs.

We hypothesize that: (i) small molecule

plasticizers will increase molecular mobility of amorphous drug-polymer dispersions and accelerate drug crystallization, and (ii) the coupling between mobility and crystallization will be unaffected at modest plasticizer concentrations (up to ~10% w/w). If our hypotheses are valid, the physical stability of unplasticized ASDs can be reliably predicted from studies of plasticized systems. 5 ACS Paragon Plus Environment


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EXPERIMENTAL SECTION Materials Ketoconazole (C26H28Cl2N4O4; purity > 98%) was a gift from Laborate Pharmaceuticals (Haryana, India). Celecoxib (C17H14F3N3O2S; form III) was purchased from Aarti Drugs Ltd. (Maharashtra, India). Polyvinyl pyrrolidone (Kollidon K12, BASF, Ludwigshafen, Germany) was dried at 110 °C for one hour prior to use. Glycerol was purchased from Fisher Scientific (Waltham, MA). Ketoconazole (KTZ) is a weakly basic BCS Class II compound while celecoxib (COX) is weakly acidic. Preparation of amorphous samples Melt-quenched amorphous drugs. Crystalline COX and KTZ were heated to 175 and 165 °C respectively, held for 30 s, and cooled rapidly in liquid nitrogen. The quenchcooled materials were then gently ground using a mortar and pestle, passed through 190 mesh (90 µm) sieve and stored at -20 °C in desiccators containing anhydrous calcium sulfate until further use. Sample preparation and handling were conducted in a glove box at < 5% RH (RT). The water content in the samples was confirmed to be < 0.5% w/w by Karl Fischer Titrimetry. Amorphous drugs with glycerol. Amorphous COX and KTZ, with up to 2% w/w glycerol, were prepared via solvent evaporation followed by melt quenching. COX and glycerol were dissolved in methanol and the solvent was evaporated at 40 °C under reduced pressure in a rotary evaporator (IKA-HB10, Werke GmbH, Staufen, Germany). The solid was further dried under reduced pressure overnight at room temperature, gently ground and melt-quenched. Preparation of ASDs. ASDs were prepared by solvent evaporation followed by meltquenching using the same procedure described earlier. PVP was dried at 110 °C for one hour prior to use.

The drug to polymer weight ratio was 9:1 and the glycerol

content was up to 10% w/w. Glycerol Content.

The glycerol content was determined before and after the melt-

quenching step using H1 NMR (Bruker Avance III AV-500, Billerica, MA). Glycerol 6 ACS Paragon Plus Environment

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content was quantified with respect to drug content.

No glycerol was lost during

heating. A differential scanning calorimeter (TA

Differential Scanning Calorimetry (DSC).

Instruments Q2000, New Castle, DE) equipped with a refrigerated cooling unit was used. The instrument was calibrated with indium. The samples were heated at 10 °C /min under nitrogen purge (50 ml/ min) in hermetically crimped pans (Tzero pans, TA Instruments). Fourier Transform Infrared Spectroscopy (IR). Sixty four spectra were obtained at room temperature, over the range of 3500 to 800 cm-1, with a resolution of 4 cm-1 (Vertex 80, Bruker, Billerica, MA). Dielectric Spectroscopy (DES). The molecular mobility was measured using a dielectric spectrometer (Novocontrol Alpha-AK high performance frequency analyzer, Novocontrol Technologies, Montabaur, Germany) at temperatures ranging from 25 to 100 °C in steps of 5 °C (Novocool Cryosystem) in the frequency range of 10-2 to 107 Hz. The experiments were carried out as a function of frequency at fixed temperatures. Sample powder was tightly packed between two gold-plated copper electrodes (20 mm diameter) confined by a PTFE spacer (1 mm thickness, 59.69 mm2 area and 1.036 pF capacitance).

DES data was analyzed using WinFit® software to obtain various

relaxation parameters.

The frequency dependence of

∗ ("),

the complex dielectric

permittivity, as a function of angular frequency, ω, was analyzed using the HavriliakNegami model (Equation 8), ∗ (")

where ∆ = #

= lim(≫

+

−

#,

1 ("),

=

∆%

#

+ (&('()))* (Equation 8)

is the dielectric relaxation strength with

+

= lim(≪ ε1 (ω) and

τ is the relaxation time, β and γ are shape parameters that are

used to respectively describe the symmetric and asymmetric broadening of the relaxation peaks with 4 > 0 and 47 ≤ 1.

The contribution of dc conductivity was

observed on the low frequency side of the dielectric spectra. This was taken into account by adding the conductivity component, :; /=" > , to the Havriliak-Negami equation, where :; is the dc conductivity and

>

is the vacuum permittivity. 7



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Synchrotron X-ray Diffraction (XRD).

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Isothermal crystallization studies were

conducted by storing the vials at elevated temperatures.

At specific time points

samples were removed from the oven, transferred to DSC pans (Tzero) and hermetically crimped (Tzero hermetic lid, TA Instruments, New Castle, DE) in the glove box (RH < 5%; RT). Samples were stored at -20 ℃ until analyses. The pans were mounted on custom-made holders. Experiments were performed in the transmission mode using synchrotron radiation in the 17-BM-B beam line at Argonne National Laboratory (Lemont, IL). A monochromatic X-ray beam [wavelength 0.72768 Å, beam size 250 µm (horizontal) & 160 µm (vertical)] and a two dimensional area detector (XRD-1621, PerkinElmer) were used. The sample to detector distance was set at 900 mm. A triple-bounce channel-cut Si single crystal monochromator with [111] faces polished was used, which limited the line broadening to its theoretical limit, i. e., the Darwin width. The flux of the incident X-ray was 8 x 1011 photons/sec @ 17 keV. The calibration was performed using Al2O3 (NIST, SRM-647a) standard. Laboratory source isothermal X-ray powder diffractometry (XRD).

Isothermal

crystallization kinetics of ASDs were conducted using an X-ray diffractometer (D8 ADVANCE, Bruker AXS, Madison, WI) equipped with a variable-temperature stage (TTK 450; Anton Paar, Graz-StraBgang, Austria), and a Si strip one-dimensional detector (LynxEye; Bruker AXS, Madison, WI). Cu Kα radiation (1.54 Å, 40 kV x 40mA) was used. Data were collected in the range of 10-30° 2θ with a step size of 0.02° and a dwell time of 0.5 s.

The sample was maintained under nitrogen purge during the

studies. Quantification of crystallinity (using laboratory XRD).

The fraction crystallized,

expressed as % crystallinity, was calculated using Equation 9. % ABCDEFFG=C =

'HIJH+'IK L MK+INOO'HJ PJNQ+ ILINO ;'MNIJ; 'HIJH+'IK

× 100%

(Equation 9)

By assuming that the total diffracted intensity (crystalline peak intensity + amorphous halo) remained constant throughout the isothermal crystallization process, the crystallinity index is equivalent to the fraction crystallized19.

A custom-built program

(Fortran 77; Tucson, AZ) was used for data analysis. A baseline correction was first 8 ACS Paragon Plus Environment

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applied and the amorphous halo was subtracted from the total diffracted pattern to yield the crystalline peaks. Intensities of all of the crystalline peaks between 10 and 30° 2θ were considered.

The % crystallinity was plotted as a function of time.

A spline

interpolation function was used to calculate the time for 10% drug crystallization (MATLAB R2015b, MathWorks, Natick, MA).

RESULTS AND DISCUSSION Baseline characterization There was no evidence of any residual crystallinity in the amorphous ketoconazole and celecoxib prepared with or without glycerol. Their X-ray diffraction patterns, obtained using a laboratory diffractometer, exhibited a broad halo over the angular range of 10 to 35° 2θ (supplementary information; Figure S1). The dispersions, irrespective of the glycerol composition, were also X-ray amorphous (representative patterns included in the supplementary information; Figure S1). Effect of glycerol In both amorphous COX and KTZ, there was a progressive decrease in glass transition temperature (Tg) as a function of glycerol concentration increased (Figure 1). A similar effect was observed in the ASDs. The reduction in Tg is attributed to the plasticizing effect of glycerol. crystallization.

The consequent increase in molecular mobility can facilitate

On the other hand, specific interactions such as hydrogen bonding

between drug and glycerol may lead to stabilization thereby reducing the drug crystallization propensity. One way to assess the impact of glycerol on the overall intermolecular interactions is by comparing the experimentally determined Tg values with theoretically predicted values. A positive deviation from the Tg prediction reflects a net gain in specific interactions in the system upon mixing. The glass transition temperatures of each KTZ and COX plasticized by glycerol, Tg, mix, were calculated using the Couchman-Karasz equation20: S,U'V =

WX YX &ZW[ Y[ WX &ZW[

(Equation 10) 9



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where w1 and w2 are respectively the weight fractions of the drug and glycerol and Tg1 and Tg2 are their respective glass transition temperatures.

The value of K,

constant21, is calculated from the change in heat capacity (ΔCp) at Tg of

a

the pure

components: \=

∆]^X ∆]^[

(Equation 11)

The Couchman-Karasz equation assumes no specific interactions between the components and perfect free volume additivity22. In case of the drugs, the Tg and ΔCp of KTZ and COX were experimentally determined while that of glycerol was obtained from the literature18. This then enabled the calculation of Tg of the drugs plasticized with glycerol (Figure 1a).

For the ASDs (with no glycerol), the Tg and ΔCp were

experimentally determined. The PVP-KTZ ASDs (with no glycerol) were the subject of an earlier investigation9. In case of PVP-COX ASDs, the addition of polymer, as expected, increased the Tg. The Tg,mix of the plasticized ASDs (0.5 to 5.0% w/w glycerol) were calculated (Figure 1b). In these mixtures, the ASD was considered as ‘one component’ and glycerol as the ‘second component’. In case of COX, both amorphous drug and PVP-COX ASDs, the calculated Tg values were in good agreement with the experimental values. For the KTZ systems, however, the experimental Tg values were consistently lower than the calculated values. The negative deviations could be attributed to a net loss in the specific interactions upon mixing with glycerol23. Since the experimentally determined Tg values did not exhibit a positive deviation from the calculated values, it is reasonable to assume that glycerol does not specifically interact with the components of ASD.

Spectroscopic investigation of drug-polymer-plasticizer interactions Hydrogen bonding between drug and polymer is a well-known mechanism for stabilization of drug in ASD23. If the addition of glycerol weakens the strength of drugpolymer interactions, then the underlying stabilization mechanism of the polymer is


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affected. IR spectroscopy was used to confirm that the glycerol did not alter the drugpolymer interactions in ASDs. The C=O bond stretching in PVP shifted from 1674 cm-1 in the physical mixture to 1660 cm-1 in the ASD, reflecting hydrogen bonding interactions between COX and PVP in the latter (Figure 2a). Addition of glycerol to the ASDs, up to 10% w/w, did not alter the C=O bond absorption peak suggesting that it did not impact the drug-polymer hydrogen bonding. In the PVP-KTZ ASDs, since there was no specific interaction between the drug and the polymer, IR studies would not be relevant.

Figure 1. Effect of glycerol concentration on the glass transition temperatures of (a) amorphous celecoxib (COX), ketoconazole (KTZ), and (b) PVP-KTZ and PVPCOX ASDs.

Figure 2. FTIR spectra of (a) PVP-COX physical mixture and ASD and (b) PVPCOX ASDs with different glycerol concentrations. 11 ACS Paragon Plus Environment


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Molecular mobility Dielectric spectroscopy (DES) was used to characterize the molecular mobility in the drugs as well as their ASDs. Representative dielectric spectra (normalized permittivity loss vs. frequency), collected in the supercooled state, are presented in Figure 3. For amorphous KTZ, a well resolved α-relaxation peak was observed (Figure 3a). This cooperative mobility mode, responsible for glass transition, is also known as global motion24. The Havriliak-Negami function was used to obtain the α-relaxation times ( ) (Figure 4; discussed later)16. The addition of glycerol, in a concentration dependent manner, progressively increased the molecular mobility, which was reflected by a shift in the α-relaxation peak to higher frequencies. In an earlier investigation, the addition of water caused a pronounced increase in dc-conductivity contribution to the low frequency region of the spectrum11. No such effect was observed with glycerol. In the PVP-KTZ ASDs, again, only a single α-relaxation peak was observed in the supercooled state (Figure 3c). The effect of glycerol on molecular mobility of the ASD was qualitatively similar to that on the drug alone (compare Figures 3a and 3c). Similar results were obtained for COX and PVP-COX ASDs (Figures 3b and 3d).


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Figure 3. Dielectric loss spectra (permittivity vs. frequency) of (a) amorphous KTZ, (b) amorphous COX, (c) PVP-KTZ ASDs and (d) PVP-COX ASDs with different glycerol concentrations.



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Temperature dependence of α-relaxation time The temperature dependence of α-relaxation time is evident from Figure 4.

In

amorphous KTZ, with increase in temperature the α-relaxation time decreased, indicating increased molecular mobility (Figure 4a). With increasing concentrations of glycerol, there was a progressive decrease in α-relaxation time.

Similar results were

seen in PVP-KTZ ASDs (Figure 4c) and in COX (Figure 4b), and PVP-COX ASDs (Figure 4d).

The temperature dependence of α-relaxation time, , is well described

by Vogel-Fulcher-Tammann (VFT) equation25: b

= > exp ( d c )

(Equation 12)

c

where > is the relaxation time constant for unrestricted materials (10-14 s), D is the strength parameter and T0 is the Kauzmann or zero mobility temperature. The fitted parameters (DT0 and T0) are presented in Table 1. In amorphous KTZ and PVP-KTZ ASDs with different concentrations of glycerol, the strength parameters (D) appeared to be independent of the glycerol concentration (Table 1). All these systems were considered ‘fragile’ based on the low value of D.

Qualitatively similar results were

observed in COX and PVP-COX ASDs. The dielectric Tg, defined as the temperature at which is 100 seconds, was obtained from the VFT fits.

These were consistently lower than the calorimetric Tg values

determined experimentally.

Plots of as a function of temperature, scaled for

dielectric Tg, are presented in Figure 5. With addition of glycerol, in both KTZ and KTZ ASDs, the temperature dependence of relaxation times when scaled for dielectric Tg, superimposed (Figures 5a and 5c). The increase in molecular mobility is therefore explained by the “plasticization” effect of glycerol.

Qualitatively similar results were

observed in COX and PVP-COX ASDs (Figures 5b and 5d).


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Figure 4. Temperature dependence of α-relaxation times of (a) amorphous KTZ, (b) amorphous COX, (c) PVP-KTZ ASDs and (d) PVP-COX ASDs with and without glycerol obtained using DES.



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Table 1. VFT parameters for amorphous KTZ, COX, PVP-KTZ and PVP-COX ASDs with different glycerol content. Glycerol

DT0

1

T0 (K)

1

D

1

(%w/w) KTZ

COX

PVP-KTZ

Tg,

(°C)

(°C)

calorimetric

0

1987 (1893, 2082)

2

0.5

2082 (1971, 2194)

2

249.1 (253.2, 256.0)

2

8.4

32.5

40.2 ± 0.2

1

1849 (1688, 2010)

2

255.0 (248.3, 261.6)

2

7.3

32.0

38.7 ± 0.4

2

2097 (2000, 2195)

2

242.8 (235.3, 243.4)

2

8.6

26.6

29.1 ± 0.5

0

1677 (1469, 1885)

2

283.9 (276.1, 291.7)

2

5.9

56.3

56.6 ± 0.3

0.5

1756 (1154, 2357)

2

279.7 (255.3, 304.0)

2

6.3

54.2

55.9 ± 0.4

1

1913 (1771, 2054)

2

270.5 (265.6, 275.3)

2

7.1

49.3

51.7 ± 0.3

2

2462 (-2432, 7357)

9.8

45.0

50.0 ± 0.3

0

2034 (2013, 2055)

2

2242 (2082, 2401)

2

2084 (1912, 2256)

2

0

1843 (1759, 1927)

2

1

2012 (1899, 2124)

2 5

1 2 PVP-COX

Tg, dielectric

2

256.8 (253.0, 260.5)

2

7.7

37.6

45.0 ± 0.5

251.3 (80.0, 422.6)

2

3 3 3 3 3 3 3 3

261.0 (261.1, 261.8)

2

7.8

43.1

40.0 ± 0.7

244.8 (238.4, 252.1)

2

9.2

32.5

35.2 ± 0.5

243.4 (236.8, 249.9)

2

8.6

26.8

28.7 ± 0.2

284.9 (276.8, 283.0)

2

6.5

61.8

60.5 ± 0.6

3

2

275.9 (271.8, 280.0)

2

7.3

57.4

55.8 ± 1.0

3

1957 (1862, 2051)

2

274.7 (271.1, 278.4)

2

7.1

54.7

52.0 ± 1.1

3

2175 (1845, 2505)

2

250.0 (237.4, 262.5)

2

8.7

35.9

43.0 ± 0.5

3

1

The values were obtained from fitting Eq. 4 to the relaxation time data.

confidence interval of fitting.

2

95%

3

Standard deviation from experimental measurements;

n=3.


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Figure 5. Plots of ef as a function of temperature, scaled for dielectric Tg. (a) amorphous KTZ, (b) amorphous COX, (c) PVP-KTZ ASDs and (d) PVP-COX ASDs. Each system was plasticized with glycerol (up to 2% w/w).



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Non-isothermal crystallization Representative DSC curves of amorphous COX, KTZ and their ASDs are presented in Figure 6. In amorphous KTZ, glass transition was observed at ~45 °C (Figure 6a and Table 2). This was followed by an exotherm attributable to crystallization (Tc), with onset at ~109 °C, and then melting (Tm; peak temperature) at ~148 °C. Increase in glycerol content progressively decreased the glass transition, crystallization and melting temperatures.

For any given glycerol content, the magnitude of decrease in Tc was

higher than the shift in Tm. Similar results were obtained for COX (Figure 6b). The addition of PVP (10% w/w) to KTZ resulted in a decrease in Tg to 40 °C. Rumondor et al had also reported that the Tg of PVP-KTZ (10% w/w; K-29) was lower than that of KTZ26. When glycerol was added to the dispersion, for any given glycerol content, the magnitude of decrease in Tc was higher than the shift in Tm (Figure 6c). The addition of PVP to COX caused an increase in the Tg to 60 °C. The effect of glycerol on the crystallization behavior was qualitatively similar for the COX and KTZ dispersions (compare figures 6c and 6d; Table 2). Its effect on the drug crystallization propensity in the different systems can be compared based on the concept of reduced temperature (Tr), defined as,27 ij dik

Th = i

l dik

(Equation 13)

This approach enables a comparison of the crystallization propensity of compounds with different melting and glass transition temperatures. Additionally, it is also possible to compare systems with different compositions. When comparing amorphous KTZ and COX with their respective ASDs, addition of PVP increased the Tr values, reflecting a reduction in crystallization propensity. The effect of PVP was more pronounced in COX than in KTZ. The addition of glycerol slightly decreased the Tr values in most but not all systems, indicating an increase in crystallization propensity brought about by the plasticizer.

However, one limitation of using Tr values for comparing crystallization

propensity became evident when COX crystallized as a mixture of polymorphic forms III and IV in PVP-COX ASDs28. Two melting endotherms were present in PVP-COX DSC curves (a shallow endotherm at ~ 146 °C (Form IV) and a pronounced peak at ~160 °C


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(Form III)) (supplementary information; Figure S2).

Since III was the predominant

polymorph, Tm value of ~160 °C was used for our calculations.

Figure 6. DSC heating curves of (a) amorphous KTZ, (b) amorphous COX, (c) PVPKTZ ASDs, and (d) PVP-COX ASDs.



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Table 2. Non-isothermal crystallization behavior of amorphous KTZ, COX, PVPKTZ and PVP-COX ASDs with different glycerol content.

KTZ

COX

PVP-KTZ

PVP-COX

Glycerol (%w/w)

Tg, calorimetric (°C)

0

45.0 ± 0.5

0.5

Tc, (°C)

Tm, (°C)

Tr

109.3 ± 2.0

148.2 ± 0.3

0.62 ± 0.02

40.2 ± 0.2

98.0 ± 0.2

146.6 ± 0.1

0.54 ± 0.00

1

38.7 ± 0.4

96.0 ± 0.2

145.6 ± 0.1

0.54 ± 0.01

2

29.1 ± 0.5

89.1 ± 0.1

141.4 ± 0.3

0.53 ± 0.01

0

56.6 ± 0.3

93.6 ± 0.2

164.9 ± 0.4

0.32 ± 0.00

0.5

55.9 ± 0.4

90.7 ± 0.8

164.4 ± 0.3

0.34 ± 0.01

1

51.7 ± 0.3

91.4 ± 0.1

164.4 ± 0.1

0.36 ± 0.00

2

50.2 ± 0.3

83.4 ± 0.2

161.2 ± 0.1

0.30 ± 0.00

0

40.0 ± 0.7

110.1 ± 0.4

146.7 ± 0.4

0.66 ± 0.01

0.5

36.9 ± 0.4

104.0 ± 0.5

143.8 ± 0.3

0.63 ± 0.01

1

35.2 ± 0.5

102.6 ± 0.3

143.6 ± 0.1

0.62 ± 0.01

2

28.7 ± 0.2

92.1 ± 0.1

139.7 ± 0.1

0.57 ± 0.00

0

60.5 ± 0.6

117.9 ± 0.4

161.1 ± 0.1

0.57 ± 0.01

0.5

57.4 ± 0.5

115.7 ± 0.1

160.2 ± 0.1

0.57 ± 0.01

1

55.8 ± 1.0

110.9 ± 0.1

158.8 ± 0.0

0.53 ± 0.01

2

52.1 ± 1.1

103.7 ± 0.1

157.7 ± 0.1

0.49 ± 0.01

5

43.0 ± 0.5

93.8 ± 0.2

152.9 ± 0.1

0.46 ± 0.01

Isothermal crystallization When stored in the supercooled state, the crystallization behavior of the dispersions depended on the glycerol content. While the two dimensional synchrotron XRD images of the ASDs were collected, for the sake of clarity, the corresponding 1D patterns are presented in Figure 7. In absence of glycerol, PVP-KTZ ASD remained amorphous after 14 days of storage at 45 °C (Figure 7a). As the concentration of glycerol in the system increased, there was a progressive increase in peak intensity, denoting an increase in drug crystallinity. Similar results were observed for the PVP-COX ASDs (Figure 7b). 20 ACS Paragon Plus Environment

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Figure 7. One dimensional XRD patterns obtained from the 2D synchrotron XRD images. (a) PVP-KTZ and (b) PVP-COX ASDs, after storage at 45℃ ℃ for 14 days and at 75℃ ℃ for 96 hours for the two drug systems respectively.

Coupling between molecular mobility and crystallization Using a laboratory XRD, crystallization of PVP-COX ASD (with up to 2% glycerol) was carried out under isothermal conditions, at four temperatures between 80 and 100 °C (supplementary information, Figure S3). The fraction crystallized was first calculated using Equation 9 and then the time for 10% drug crystallization (t10%) was determined. As pointed out earlier, we had determined the α-relaxation time of these systems between 70 and 100 °C.

It was therefore possible to plot t10% as a function of α-

relaxation time (Figure 8).

The coupling between molecular mobility ( ) and

crystallization time (t10%) was determined using Equation 7. The M value (coupling coefficient) for the ASD (without glycerol) is 0.80 (Figure 8a), indicating that crystallization is well coupled to α-relaxation time. For the ASD with 1% and 2% w/w glycerol, the M values were 0.88 and 0.78 respectively (Figure 8b and 8c).

In the

temperature range of this study, the extent of coupling between mobility and crystallization for ASDs with and without glycerol remained reasonably similar. Similarly, the y-intercept (‘A’ in Equation 7), a constant related to the thermodynamic driving force of crystallization, was also approximately the same. This suggested that



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the acceleration in crystallization for the plasticized systems was accounted for by the increase in molecular mobility.

Figure 8. A plot of time for 10% crystallization vs. α-relaxation time of PVP-COX ASDs with 0 to 2% w/w glycerol.

Physical stability prediction Molecular mobility has previously been used to predict the crystallization behavior of both amorphous pharmaceuticals and ASDs. Bhugra et al. established the coupling between molecular mobility and crystallization of indomethacin and flopropione in the supercooled state29-30.

Using this information, they attempted to predict their

crystallization onset times in the glassy state from their mobility measurements. This approach was based on two assumptions. (i) The coupling between molecular mobility and crystallization is the same in the glassy and supercooled states. (ii) The structural relaxation time value (the measure of molecular mobility) is independent of the measurement technique.

This assumption was necessitated because they used

modulated DSC and isothermal calorimetry to measure mobility in the glassy state and dielectric spectroscopy in the supercooled state.

Excellent quantitative agreement

between the predicted and experimental crystallization onset times were observed for florpropione. The approach, when extended to ASDs, was unsuccessful. The authors pointed out that the coupling between mobility and crystallization in the glassy and supercooled states may not be the same31. This was supported by our results with nifedipine-PVP dispersions wherein the coupling coefficient value was determined to be much higher in the glassy state32.

It may, therefore, be inappropriate to use the 22


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coupling coefficient determined in the supercooled state to predict crystallization behavior in ASDs in the glassy state. On the other hand, earlier investigations suggest that the coupling between molecular mobility and crystallization can be used to predict the crystallization behavior in ASDs with modest differences in composition.

In nifedipine-PVP ASDs7 the structural

relaxation time was well coupled to crystallization time (t10%). More importantly, in a limited polymer concentration range (2.5 to 20% w/w), the coupling was essentially unaltered. However, the addition of polymer, in a concentration dependent manner, increased the free-energy barrier for drug crystallization.

This was reflected by an

increase in the value of the term “A” in the coupling equation (Equation 7). The authors attempted to predict the crystallization times (t10%) of ASDs with higher PVP content using the coupling coefficient obtained for the ASD with 2.5% PVP. This entailed the several steps. First, the coupling coefficient between molecular mobility and crystallization time was determined for ASD with 2.5% w/w PVP. Then, at a selected temperature, the crystallization times of the ASDs with higher polymer concentrations (5 and 10%) were determined thereby obtaining the value of the term “A” (Equation 7) for these systems. The crystallization times were predicted using the coupling equations and the experimentally determined relaxation times. The predicted and experimental results were in good agreement. Recently, the approach was extended to predict stability of ketoconazole ASDs prepared with each polyacrylic acid (PAA), poly(2-hydroxyethyl methacrylate) (PHEMA) and PVP. The three polymers differed widely in their strength of interaction with KTZ. Though the polymer concentration was low (only 4% w/w), the coupling coefficient (the coupling between mobility and crystallization) value depended on the specific polymer. For the PAA dispersion, the value was close to that of the KTZ alone but not for the ASDs prepared with the other two polymers. The addition of polymer, even at a low concentration, can substantially decelerate drug crystallization. In an effort to determine the specific influence of each of these polymers on KTZ crystallization, the coupling coefficient determined for KTZ was used to predict the crystallization behavior of the ASDs.

The predicted crystallization times (t2%) were in good agreement with the 23 ACS Paragon Plus Environment


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experimental values for PAA ASD. However, for the PHEMA and PVP ASDs, there was a deviation attributable to the difference in the coupling coefficient value of the drug from that of these ASDs. This suggests that when the coupling coefficient for the drug and dispersion are close (as in PAA ASD), the value obtained for the drug can be used to reliably predict the behavior of the dispersion. In our study, the addition of a small amount of glycerol (up to 2% w/w), accelerated COX crystallization in ASDs without affecting the values of either the coupling coefficient or the parameter “A” (Equation 7). It therefore seemed appropriate to predict the crystallization times of PVP-COX ASD (unplasticized system) using the coupling equation obtained from the glycerol-plasticized systems. The estimated crystallization times (t10%) at 85, 90, 95 and 100 °C were calculated using the experimentally measured α-relaxation times for PVP-COX (unplasticized system) and the coupling equation obtained for the plasticized ASD (with 2% w/w glycerol; Table 3).

The

predicted values were in good agreement with the experimental results. Table 3. Comparison of the predicted and experimental crystallization times in PVP-COX ASD. Temperature (℃ ℃)

Time for 10% drug crystallization Predicted (h)

Experimental (h)

85

10.7

9.8 ± 1.7

90

2.8

3.7 ± 0.5

95

0.9

0.7 ± 0.0

100

0.3

0.3 ± 0.1

These preliminary results, while limited in scope, are quite promising. The utility of this technique needs to be established using a variety of model drug compounds and different plasticizers. More importantly, our current study was carried out in the supercooled region. ASDs are likely to be stored in the glassy state. Therefore, it is important to establish the validity of the technique in the glassy state. As a first step, it will be necessary to establish the coupling between mobility and crystallization in the glassy state. However, there are a few potential complications. (i) The use of glycerol, 24 ACS Paragon Plus Environment

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at a low concentration, has been reported to exert an anti-plasticizing effect in glasses, both in small molecule and in a polymer (maltodextrin and sucrose)33-34. In such cases, this approach will not be effective. However, our preliminary results indicate that addition of glycerol accelerated crystallization of glassy KTZ and COX (supplementary information; Figure S4). (ii) In the glassy state, crystallization may not be coupled to αrelaxation time. In fact, recent studies suggest that crystallization of glassy COX and indomethacin are coupled to β-relaxation (local mobility)35. SIGNIFICANCE The potential for drug crystallization is an important factor governing the design, development and manufacture of ASDs. An additional challenge is our limited ability to predict drug crystallization behavior (onset, kinetics) in ASDs. We had earlier observed that the addition of small amounts of water increased molecular mobility and accelerated drug crystallization in ASDs10. Building on that information, we have now established that the molecular mobility of ASDs, with up to 2% w/w glycerol, was well coupled to crystallization. The acceleration in crystallization brought about by glycerol enabled us to establish the mobility-crystallization coupling in short timescales. More importantly, the crystallization behavior in plasticized systems enabled the prediction, with reasonable accuracy, of crystallization times in unplasticized ASDs. This approach provides an avenue to predict the physical stability of “slow crystallizing” systems.

For

example, in ASD formulations with high polymer content, glycerol may be used to (i) accelerate crystallization, thereby facilitate the determination of the coupling between crystallization and molecular mobility and (ii) serve as a tool for physical stability prediction. CONCLUSIONS We demonstrated that the addition of glycerol, in a concentration dependent manner, increased the molecular mobility (decrease in α-relaxation time) and decreased the physical stability of amorphous ketoconazole (KTZ) and celecoxib (COX). The same effect was also observed in PVP-KTZ and PVP-COX amorphous solid dispersions (ASDs). The extent of coupling between molecular mobility and crystallization in PVP-



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COX ASDs remained the same at up to 2% w/w glycerol concentration. As a result, the behavior of the rapidly crystallizing plasticized system was used to predict, with reasonable accuracy, the crystallization behavior of the dry ASD. ASSOCIATED CONTENT Supporting Information Figures containing (i) XRD patterns of systems with and without glycerol immediately after preparation, (ii) DSC heating curve of PVP-COX ASD, (iii) isothermal XRD patterns at 85 °C, as a function of time, of PVP-COX ASD containing 2% w/w glycerol, and (iv) one dimensional XRD patterns obtained from the 2D synchrotron XRD images of amorphous COX and KTZ, with up to 2% w/w glycerol after storage at room temperature. A table containing the parameters for Tg prediction of amorphous samples with and without glycerol.

AUTHOR INFORMATION Corresponding Author *Address: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, United States. E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS M.H.F was partially supported by PhRMA Pre-Doctoral Fellowship in Pharmaceutics and the Rowell Graduate Fellowship, University of Minnesota. This project was partially funded by the William and Mildred Peters Endowment Fund. Powder XRD work was carried out at the Characterization Facility, University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Contract No. DE-AC02-06CH11357. We 26 ACS Paragon Plus Environment

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thank Dr. Wenqian Xu and Dr. Gregory Halder at Argonne National Laboratory for their help during the synchrotron data collection. Heelim Li is thanked for her help in sample preparation for synchrotron studies. The authors would like to thank Mehak Mehta, Kārlis Bērziņš and Pinal Mistry for the helpful discussions and comments.



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REFERENCES 1. Adachi, M.; Hinatsu, Y.; Kusamori, K.; Katsumi, H.; Sakane, T.; Nakatani, M.; Wada, K.; Yamamoto, A., Improved dissolution and absorption of ketoconazole in the presence of organic acids as pH-modifiers. European Journal of Pharmaceutical Sciences 2015, 76, 225-230. 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 (23), 1068-1075. 3. Kawabata, Y.; Wada, K.; Nakatani, M.; Yamada, S.; Onoue, S., Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications. International Journal of Pharmaceutics 2011, 420 (1), 1-10. 4. Ngai, K.; Magill, J.; Plazek, D., Flow, diffusion and crystallization of supercooled liquids: Revisited. The Journal of Chemical Physics 2000, 112 (4), 1887-1892. 5. Yoshioka, S.; Aso, Y., Correlations between molecular mobility and chemical stability during storage of amorphous pharmaceuticals. Journal of Pharmaceutical Sciences 2007, 96 (5), 960-981. 6. Bhardwaj, S. P.; Arora, K. K.; Kwong, E.; Templeton, A.; Clas, S.-D.; Suryanarayanan, R., Correlation between molecular mobility and physical stability of amorphous itraconazole. Molecular Pharmaceutics 2013, 10 (2), 694-700. 7. Kothari, K.; Ragoonanan, V.; Suryanarayanan, R., The Role of Polymer Concentration on the Molecular Mobility and Physical Stability of Nifedipine Solid Dispersions. Molecular Pharmaceutics 2015. 8. Mistry, P.; Mohapatra, S.; Gopinath, T.; Vogt, F. G.; Suryanarayanan, R., Role of the strength of drug-polymer interactions on the molecular mobility and crystallization inhibition in ketoconazole solid dispersions. Molecular Pharmaceutics 2015. 9. Mistry, P.; Suryanarayanan, R., Strength of Drug–Polymer Interactions: Implications for Crystallization in Dispersions. Crystal Growth & Design 2016. 10. Mehta, M.; Kothari, K.; Ragoonanan, V.; Suryanarayanan, R., Effect of Water on Molecular Mobility and Physical Stability of Amorphous Pharmaceuticals. Molecular Pharmaceutics 2016, 13 (4), 1339-1346. 11. Mehta, M.; Suryanarayanan, R., Accelerated Physical Stability Testing of Amorphous Dispersions. Molecular Pharmaceutics 2016, 13 (8), 2661-2666. 12. Noel, T. R.; Parker, R.; Ring, S. G., Effect of molecular structure and water content on the dielectric relaxation behaviour of amorphous low molecular weight carbohydrates above and below their glass transition. Carbohydrate Research 2000, 329 (4), 839-845. 13. Schmitt, E.; Davis, C.; Long, S., Moisture-dependent crystallization of amorphous lamotrigine mesylate. Journal of Pharmaceutical Sciences 1996, 85 (11), 1215-1219. 14. Rumondor, A. C.; Taylor, L. S., Effect of polymer hygroscopicity on the phase behavior of amorphous solid dispersions in the presence of moisture. Molecular Pharmaceutics 2010, 7 (2), 477-490. 15. Hodge, R.; Bastow, T.; Edward, G.; Simon, G.; Hill, A., Free volume and the mechanism of plasticization in water-swollen poly (vinyl alcohol). Macromolecules 1996, 29 (25), 8137-8143. 16. Kremer, F.; Schönhals, A., Broadband Dielectric Spectroscopy. Springer: 2003. 17. Ghebremeskel, A. N.; Vemavarapu, C.; Lodaya, M., Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: selection of polymer–surfactant combinations using solubility parameters and testing the processability. International Journal of Pharmaceutics 2007, 328 (2), 119129. 18. Pouplin, M.; Redl, A.; Gontard, N., Glass transition of wheat gluten plasticized with water, glycerol, or sorbitol. Journal of Agricultural and Food Chemistry 1999, 47 (2), 538-543. 19. Nunes, C.; Mahendrasingam, A.; Suryanarayanan, R., Quantification of crystallinity in substantially amorphous materials by synchrotron X-ray powder diffractometry. Pharm Res 2005, 22 (11), 1942-1953. 28 ACS Paragon Plus Environment

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20. Couchman, P.; Karasz, F., A classical thermodynamic discussion of the effect of composition on glass-transition temperatures. Macromolecules 1978, 11 (1), 117-119. 21. Gordon, J.; Rouse, G.; Gibbs, J.; Risen Jr, W. M., The composition dependence of glass transition properties. The Journal of Chemical Physics 1977, 66 (11), 4971-4976. 22. Hancock, B. C.; Zografi, G., The relationship between the glass transition temperature and the water content of amorphous pharmaceutical solids. Pharm Res 1994, 11 (4), 471-477. 23. Kothari, K.; Ragoonanan, V.; Suryanarayanan, R., The Role of Drug–Polymer Hydrogen Bonding Interactions on the Molecular Mobility and Physical Stability of Nifedipine Solid Dispersions. Molecular Pharmaceutics 2015, 12, 162-170. 24. Angell, C. A., Formation of glasses from liquids and biopolymers. Science 1995, 267 (5206), 19241935. 25. Böhmer, R.; Ngai, K.; Angell, C.; Plazek, D., Nonexponential relaxations in strong and fragile glass formers. The Journal of Chemical Physics 1993, 99 (5), 4201-4209. 26. Rumondor, A. C.; Ivanisevic, I.; Bates, S.; Alonzo, D. E.; Taylor, L. S., Evaluation of drug-polymer miscibility in amorphous solid dispersion systems. Pharm Res 2009, 26 (11), 2523-2534. 27. Zhou, D.; Zhang, G. G.; Law, D.; Grant, D. J.; Schmitt, E. A., Physical stability of amorphous pharmaceuticals: importance of configurational thermodynamic quantities and molecular mobility. Journal of Pharmaceutical Sciences 2002, 91 (8), 1863-1872. 28. Lu, G. W.; Hawley, M.; Smith, M.; Geiger, B. M.; Pfund, W., Characterization of a novel polymorphic form of celecoxib. Journal of Pharmaceutical Sciences 2006, 95 (2), 305-317. 29. Bhugra, C.; Shmeis, R.; Krill, S. L.; Pikal, M. J., Predictions of onset of crystallization from experimental relaxation times I-correlation of molecular mobility from temperatures above the glass transition to temperatures below the glass transition. Pharm Res 2006, 23 (10), 2277-2290. 30. Bhugra, C.; Shmeis, R.; Krill, S. L.; Pikal, M. J., Prediction of onset of crystallization from experimental relaxation times. II. Comparison between predicted and experimental onset times. Journal of Pharmaceutical Sciences 2008, 97 (1), 455-472. 31. Caron, V.; Bhugra, C.; Pikal, M. J., Prediction of onset of crystallization in amorphous pharmaceutical systems: phenobarbital, nifedipine/PVP, and phenobarbital/PVP. Journal of Pharmaceutical Sciences 2010, 99 (9), 3887-3900. 32. Kothari, K.; Ragoonanan, V.; Suryanarayanan, R., Influence of Molecular Mobility on the Physical Stability of Amorphous Pharmaceuticals in the Supercooled and Glassy States. Molecular Pharmaceutics 2014. 33. Roussenova, M.; Murith, M.; Alam, A.; Ubbink, J., Plasticization, antiplasticization, and molecular packing in amorphous carbohydrate-glycerol matrices. Biomacromolecules 2010, 11 (12), 3237-3247. 34. You, Y.; Ludescher, R. D., The effect of glycerol on molecular mobility in amorphous sucrose detected by phosphorescence of erythrosin B. Food Biophysics 2007, 2 (4), 133-145. 35. Mehta, M.; Ragoonanan, V.; McKenna, G. B.; Suryanarayanan, R., Correlation between Molecular Mobility and Physical Stability in Pharmaceutical Glasses. Molecular Pharmaceutics 2016, 13 (4), 1267-1277.



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For Table of Contents Use Only

The use of a plasticizer for physical stability prediction of amorphous solid dispersions Michelle H. Fung1, Raj Suryanarayanan1* 1

Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota

55455, USA *Corresponding Author: Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, United States. Phone: 612-624-9626. Fax: 612-6262125. E-mail: [email protected]

Utilizing glycerol as a plasticizer, an accelerated physical stability testing method of amorphous solid dispersions (ASD) was developed. The acceleration in crystallization brought about by glycerol expedited the determination of the coupling between molecular mobility and crystallization.

The behavior of the rapidly crystallizing

plasticized system was used to predict the crystallization behavior of the dry ASD.


Use of a Plasticizer for Physical Stability Prediction of Amorphous

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