Investigating the Correlation between Miscibility and Physical Stability

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Investigating the Correlation between Miscibility and Physical Stability of Amorphous Solid Dispersions Using Fluorescence-based Techniques Bin Tian, Xing Tang, and Lynne S. Taylor Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.6b00803 • Publication Date (Web): 04 Oct 2016 Downloaded from http://pubs.acs.org on October 7, 2016

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Molecular Pharmaceutics

Investigating the Correlation between Miscibility and Physical Stability of Amorphous Solid Dispersions Using Fluorescence-based Techniques Bin Tiana,b, Xing Tang a*, Lynne S. Taylor b* *: Corresponding author a

: Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Wenhua Road

103, Shenyang 110016, People's Republic of China b

: Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University,

West Lafayette, Indiana 47907, United States E-mail: Bin Tian: [email protected] Xing Tang: [email protected] Lynne S. Taylor: [email protected]

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Abstract: The purpose of this study was to investigate the feasibility of using a fluorescencebased technique to evaluate drug-polymer miscibility and to probe the correlation between miscibility and physical stability of amorphous solid dispersions (ASDs). Indomethacinhydroxypropyl methylcellulose (IDM-HPMC), indomethacin-hydroxypropyl methylcellulose acetate succinate and indomethacin-polyvinylpyrrolidone (IDM-PVP) were used as model systems. The miscibility of the IDM-polymer systems was evaluated by fluorescence spectroscopy, fluorescence imaging, differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The physical stability of IDM-polymer ASDs stored at 40 °C was evaluated using fluorescence imaging and X-ray diffraction (XRD). The experimentally determined miscibility limit of IDM with the polymers was 50%~60%, 20%~30% and 70%~80% drug loading for HPMC, HPMCAS and PVP respectively. The X-ray results showed that for IDM-HPMC ASDs, samples with a drug loading of less than 50% were maintained in amorphous form during the study period, while samples with drug loadings higher than 50% crystallized within 15 days. For IDMHPMCAS ASDs, samples with drug loading less than 30% remained amorphous, while samples with drug loadings higher than 30% crystallized within 10 days. PVP ASDs were found to be resistant to crystallization for all compositions. Thus a good correlation was observed between phase separation and reduced physical stability, suggesting that miscibility is indeed an important ASDs characteristic. In addition, fluorescence-based techniques show promise in the evaluation of drug-polymer miscibility.

Keywords:

amorphous solid dispersion, miscibility, fluorescence, physical stability

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Introduction The amorphous form of a drug has higher solubility and a faster dissolution rate as compared with its crystalline counterpart due to its higher free energy, and can potentially improve the oral bioavailability of poorly water-soluble drugs.1, 2 However, amorphous drugs tend to crystallize with time, thereby negating any solubility and dissolution rate enhancements.3 To prevent crystallization, amorphous drugs are typically molecularly dispersed in an amorphous polymer, generating a system referred to as an amorphous solid dispersion (ASD).4, 5 ASDs have been widely used as a strategy to enhance the solubility, dissolution rate and bioavailability of poorly water-soluble drugs, and there are a number of commercial products based on ASDs.6 Due to the importance of polymers in preventing crystallization of the amorphous drug, polymer selection is a critical component of ASD formulation. It has been suggested that solubility and miscibility are important factors influencing the physical stability of a drug formulated as an ASD.7 In this context, the terms solubility and miscibility can be considered as the crystal solubility and amorphous solubility of the drug in the polymer matrix respectively, making the assumption that the polymer is a solvent for the drug. For an ASD with a drug loading lower than the crystal solubility, the system is thermodynamically stable and no crystallization will occur. Unfortunately, predicted and experimental results suggest that the solubility of a crystalline drug in an amorphous polymer is virtually always too low to meet practical needs.8-11 For an ASD with a drug loading higher than the miscibility limit, amorphousamorphous phase separation is thermodynamically favored, leading to the formation of a drugrich phase. In turn, crystallization from the drug-rich phase is anticipated to occur due to a reduced polymer concentration in this phase, leading to decreased dissolution performance, ultimately impacting bioavailability.4, 12, 13 Finally, for an ASD with a drug loading between the solubility and miscibility limits, there is a thermodynamic driving force for crystallization, but not amorphous-amorphous phase separation, and the drug may remain in the amorphous phase due to the very slow kinetics of nucleation and growth in the drug-polymer glassy matrix.14, 15 Based on the above evaluation, it is clear that the polymer selected for the ASD formulation should be miscible with the drug to ensure the physical stability of the resultant ASD. Unfortunately, it is often challenging to evaluate drug-polymer miscibility although various techniques have been used for this purpose.16 The characterization of drug-polymer miscibility is 1 ACS Paragon Plus Environment


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based on the fact that amorphous-amorphous phase separation can occur at certain drug:polymer ratios when the miscibility limit is exceeded, leading to the presence of two phases, a drug-rich phase, and a polymer-rich phase which can be either directly detected, or inferred with some techniques.17 The most commonly used technique is probably differential scanning calorimetry (DSC). Typically, if only a single glass transition temperature (Tg) event is observed, the drugpolymer system is thought to be miscible, and if more than one Tg event is observed, the system is considered to have two phases.18 However, if the domain size of the separated phase is very small (less than 30 nm) or the separated phases have similar Tgs or remix during heating, it is challenging to detect phase separation using DSC.16, 19 Hence, it has been reported that a single Tg was observed for a phase-separated system and two Tgs were observed for a miscible system.20,

21

Imaging techniques, such as scanning electron microscopy (SEM), transmission

electron microscopy (TEM), and atomic force microscopy (AFM) have been employed to evaluate drug-polymer miscibility.22, 23 These techniques can provide high spatial resolution at the nanoscale, but cannot chemically identify each phase. Consequently, additional techniques including infrared (IR) spectroscopy, thermal analysis and Lorentz contact resonance mechanical measurement have been combined with AFM to overcome these issues.24, 25 Raman mapping is another technique that has been used to evaluate drug-polymer miscibility.11,

20, 23, 26

This

technique enables characterization of the chemical composition of different phases, but can be slow and it may be difficult to achieve the required spatial resolution.27 In addition, X-ray diffraction (XRD), IR spectroscopy and solid state nuclear magnetic resonance (ssNMR) spectroscopy have been used to evaluate drug-polymer miscibility.28-30 It has been suggested that miscible ASDs should have better physical stability and hence be more resistant to crystallization.31 However, the correlation between miscibility and crystallization tendency has not been extensively investigated. The objective of this study was to investigate this issue using indomethacin (IDM) as a model compound formulated as a dispersion

with

three

different

polymers,

hydroxypropyl

methylcellulose

(HPMC),

hydroxypropyl methylcellulose acetate succinate (HPMCAS) and polyvinylpyrrolidone (PVP). The miscibility of the IDM-polymer systems was evaluated using a fluorescence-based approach that takes advantage of the autofluorescence of indomethacin, together with additional techniques. As an environment-sensitive fluorophore, IDM can be used to probe the polarity of the surrounding environment at a molecular level. If the system is miscible, IDM should be 2 ACS Paragon Plus Environment

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homogeneously dispersed in the polymer matrix, which is a more polar environment than pure amorphous IDM. However, if the drug loading exceeds the miscibility limit, phase separation should occur, producing drug-rich and polymer-rich phases. The environment of IDM in the drug-rich phase is expected to be less polar, and a change in the emission spectrum is anticipated.12 Following characterization of drug-polymer miscibility, IDM-polymer ASDs were prepared and their physical stability was evaluated to investigate the correlation between the miscibility and physical stability.

Materials and Methods Materials IDM was purchased from Letco Medical, INC. (Decatur, AL, U.S.A.). HPMC (Methocel E5) was obtained from The Dow Chemical Company (Midland, MI, U.S.A). HPMCAS (MF grade) was obtained from Shin-Etsu Chemical Co. Ltd. (Tokyo, Japan). PVP (K30) was obtained from BASF Corporation (Ludwigshafen, Germany). Methanol was purchased from Fisher Scientific International, Inc. (Geel, Belgium) and dichloromethane was purchased from Avantor Performance Materials (Phillipsburg, NJ, U.S.A.). The chemical structures of drug and polymers are shown in Figure 1.

Figure 1. Chemical structures of IDM, HPMC, PVP and HPMCAS.

Methods

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Preparation of IDM-Polymer Thin Films. IDM-polymer films were prepared using a drop casting method for fluorescence and IR measurements. IDM and polymer at different drugpolymer ratios (5:95, 10:90, 20:80, 30:70, 40:60, 50:50, 60:40, 70:30, 80:20, 90:10 and 95:5) were dissolved in a mixture of methanol and dichloromethane (1:2, v/v) to obtain a total concentration of 10 mg/mL. Then, 30 µL solution was dropped onto a quartz slide or a KRS-5 substrate and left to dry. The relative humidity was controlled to be at 20% or lower by using a nitrogen purge gas and the temperature was approximately 20 °C. The films obtained were then dried overnight in a vacuum oven at ambient temperature to remove residual solvent. Drug-only and polymer-only thin films were prepared using the same method. Preparation of Bulk ASDs. Bulk ASDs were prepared using a solvent evaporation method. IDM and polymer at different drug-polymer ratios (10:90, 20:80, 30:70, 40:60, 50:50, 60:40, 70:30, 80:20 and 90:10) were dissolved in a mixture of methanol and dichloromethane (1:2, v/v). The ASDs were prepared using a Brinkmann Rotavapor-R (Buchi, DE, U.S.A.) under reduced pressure at 60 °C to remove the solvent and the resultant dispersions were dried overnight under vacuum to remove the residual solvent. Samples were then ground using a 6750 Freezer/Mill cryogenic mill (SPEX SamplePrep, NJ, U.S.A.). Liquid nitrogen was used as a coolant. Fluorescence Spectroscopy. Fluorescence spectroscopy was used to evaluate the miscibility of IDM with the polymers. The emission spectra of freshly prepared drug-polymer thin films were recorded using a Shimadzu RF-5301PC Spectrofluorophotometer (Kyoto, Japan) over the wavelength range of 410-670 nm using an excitation wavelength of 355 nm. Selected samples were also evaluated following 5 hrs of annealing at Tg-10°C; fresh and annealed samples gave rise to similar spectra indicating that these annealing conditions did change the miscibility of the samples. The emission spectra of the quartz slide, drug-only and polymer-only thin films were also obtained as controls. Fluorescence Microscopy. To estimate the miscibility and stability of the IDM-polymer system, the thin films obtained were imaged using an Olympus BX51 fluorescence microscope (Olympus Corporation, NY, U.S.A.). Filters were used to provide excitation from 330-380 nm and emission was detected from 420 nm onward. Infrared (IR) Spectroscopy. IR spectra of the drug-polymer thin films were collected in transmission mode using a Bruker Vertex 70 FT-IR spectrophotometer (Bruker Corporation, MA, 4 ACS Paragon Plus Environment

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U.S.A.). The scan range was set from 500 to 3000 cm-1 with a resolution of 4 cm-1 and 64 scans were coadded. The detector and sample compartment were purged with conditioned air to avoid interference from moisture and CO2. DSC Measurements. The Tgs of freshly prepared bulk ASDs were determined using a TA Q2000 DSC equipped with a refrigerated cooling system (TA Instruments, DE, U.S.A.). Approximately 4 mg of sample was weighed and sealed in a Tzero aluminum pan with a pinhole in the lid. Samples were equilibrated at -10 °C, held for 1 min and then heated up to 190 °C at a heating rate of 5 °C/min with modulation of ±1 °C every 60 s. X-ray Diffraction. XRD was used to estimate the physical stability of bulk ASD powders. The XRD patterns of bulk ASDs were recorded using a SmartLab X-ray diffractometer (Rigaku Corporation, Tokyo, Japan). Measurements were performed with CuKα radiation at 40 kV and 20 mV over a 2θ range of 5-40° with a scan rate of 4°/min and a step size of 0.02°. Physical Stability Testing. The drug-polymer films and bulk ASDs were stored in desiccators over desiccant at 40 °C. Periodically, physical stability of the films and ASD powders were evaluated by fluorescence microscopy and XRD respectively.

Results IDM-Polymer Miscibility Fluorescence Spectroscopy. It is anticipated that changes in the fluorescence spectrum may occur for a fluorophore if the local environment changes. To investigate the sensitivity of IDM molecules to the local environment, solid state spectra of IDM-polymer (5% drug loading) and pure amorphous IDM were obtained from thin films as shown in Figure 2. The spectrum of the pure amorphous IDM film is blue shifted relative to the spectra of IDM-polymer films. This indicates that the emission spectrum of IDM is sensitive to its local environment and can be used as a probe to determine the miscibility of IDM-polymer systems. The spectra of HPMC, HPMCAS, PVP films and the blank quartz slide are shown for reference. Figure 3A shows the fluorescence spectra of IDM-HPMC films at different drug loadings; these spectra have been normalized with respect to the maximum intensity to allow comparison of the peak maximum. The changes in the emission maximum are shown in Figure 3B as a 5 ACS Paragon Plus Environment


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function of drug loading. It can be seen that for samples in the range of 5%~50% drug loading, the emission maximum (~515 nm) did not change significantly as a function of polymer content, with only a slight decrease with increasing drug loading, indicating that IDM molecules dispersed in these samples shared a similar local environment. Between 50 and 60% drug loading, a new peak is seen at around 480 nm, indicating a change in local environment of IDM molecules. This peak is similar to that observed in the emission spectrum of pure indomethacin and suggests the IDM molecules are in an IDM-rich environment. A shoulder remains at ~515 nm indicating that a population of the IDM molecules remain in the same environment as observed for the lower drug loading ASDs. This observed emergence of a new blue shifted peak is attributed to phase separation and the formation of an IDM-rich phase and hence a less polar environment for a portion of the IDM in the dispersion. The results of fluorescence measurements suggest that the IDM-HPMC system is miscible up to a 50% drug loading, and it undergoes phase separation at drug loadings of 60% and higher. The miscibility of limit for IDM in HPMC therefore appears to be between 50% and 60% drug loading. Figure 4 shows the normalized fluorescence spectra and the changes in emission maximum of IDM-HPMCAS films at different drug loadings. For this system, a new, blue shifted emission peak was observed for the 30% drug loading film relative to the spectrum of the 20% drug loading film. This suggests that the IDM-HPMCAS system forms a new drug-rich phase when the drug loading reaches 30%. Thus IDM appears to reach the miscibility limit in HPMCAS at a drug loading between 20% and 30%. Figure 5 shows the normalized fluorescence spectra and changes in emission maximum of IDM-PVP films at different drug loadings. The emission peak at ~480 nm, indicative of an IDMrich environment, is not observed until the drug loading reaches 80%.


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Figure 2. Fluorescence spectra of amorphous IDM, IDM-HPMC, IDM-HPMCAS, HPMC, HPMCAS films and the blank quartz slide. The drug loading in the ASD films was 5 wt.%.

Figure 3. Normalized fluorescence spectra (A) and the emission maximum (B) of IDM-HPMC films at different drug loadings (n = 3). Percentages in the legend refer to the drug loading.



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Figure 4. Normalized fluorescence spectra (A) and the emission maximum (B) of IDMHPMCAS films at different drug loadings (n = 3). Percentage s in the legend refer to the drug loading.

Figure 5. Normalized fluorescence spectra (A) and the emission maximum (B) of IDM-PVP films at different drug loadings (n = 3). Percentages in the legend refer to the drug loading. Fluorescence Imaging. Fluorescence imaging was used to study the phase separation of IDM-polymer systems according to the distribution of fluorescence intensity. The fluorescence images of IDM-HPMC, IDM-HPMCAS and IDM-PVP freshly prepared films are shown in Figure 6, Figure 7 and Figure 8 respectively. It should be noted that no birefringence could be observed for these films indicating that they contain amorphous drug. For the IDM-HPMC system, the fluorescence intensity of films with a 5%~50% drug loading is homogeneous, 8 ACS Paragon Plus Environment

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indicating that IDM is uniformly dispersed in these films. However, the fluorescence intensity becomes heterogeneous for samples with a drug loading of 60% or higher, whereby samples display green and dark domains. Due to the fluorescence of IDM, the green domains are expected to be an IDM-rich phase and the dark domains are thought to be the HPMC-rich phase. These images suggest that phase separation has occurred for these samples. On the basis of the fluorescence images, the miscibility of IDM in HPMC appears to be exceeded at drug loadings of around 60%. For the IDM-HPMCAS system, 5% and 10% drug loading films showed a homogeneous fluorescence intensity distribution, indicating that these two sample are miscible. When the drug loading increases to 20%, the fluorescence intensity is reasonably homogeneous. However, for the 30% drug loading film, some heterogeneity has evolved and for samples with higher drug loadings, phase separation is obvious. From these images, the miscibility of IDM in HPMCAS appears to be limited to around 20% drug loading. Similarly, for the IDM-PVP system, obvious heterogeneity was observed for drug loadings of 70% and higher indicating phase separation.



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Figure 6. Fluorescence images of freshly prepared IDM-HPMC films at different drug loadings. Percentages refer to the drug loading.

Figure 7. Fluorescence images of freshly prepared IDM-HPMCAS films at different drug loadings. Percentages refer to the drug loading.


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Figure 8. Fluorescence images of freshly prepared IDM-PVP films at different drug loadings. Percentages refer to the drug loading. IR Spectroscopy. IR spectroscopy was used to characterize the molecular interactions between drug and polymer molecules. It can be seen from Figure 1 that IDM contains carbonyl groups and HPMC contains hydroxyl groups, hence they can interact with each other through hydrogen bonding. The normalized IR spectra of amorphous IDM-HPMC films in the carbonyl region are shown in Figure 9. The spectrum of pure amorphous IDM is also shown for reference. Amorphous IDM has three peaks at 1733, 1709 and 1683 cm-1 in this region, which have been assigned to the free acid carbonyl group, acid carbonyl group in a cyclic dimer and amide carbonyl group respectively.32 Compared with the spectrum of pure amorphous IDM, two significant changes occurred in the spectrum of the film with a 5% drug loading. These were the increase of relative intensity of peak at 1733 cm-1 and the disappearance of the peak at 1709 cm-1. These changes indicate that HPMC can disrupt the self-interactions of IDM, notably the dimeric hydrogen bonding, accounting for the loss of the peak at 1709 cm-1. As the drug loading increases, the spectra did not change significantly until a 50% drug loading is reached. For the 60% drug loading film, the peak at 1709 cm-1 becomes apparent and the relative intensity increases with increased drug loading. This indicates the formation of carboxylic acid cyclic dimers, which 11 ACS Paragon Plus Environment


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would be consistent with phase separation and the formation of an IDM-rich phase. Consequently, the IR data supports a miscibility limit of IDM in HPMC around 50% drug loading. For the IDM-HPMCAS system, miscibility could not be easily evaluated from the IR data due to the absorption of HPMCAS in this region (data not shown). For IDM-PVP films with drug loading between 5% and 80%, the peaks at 1733 and 1709 cm-1 disappeared, and new peaks appeared at 1724 and 1640 cm-1, indicating strong interaction between IDM and PVP. For samples with higher drug loading, the IR spectra were similar to that of the pure amorphous IDM, indicating the drug-drug interactions dominate. The miscibility limit of IDM in PVP was estimated to be at least 80% drug loading and can be attributed to the strong interactions between drug and polymer. The IR spectra of IDM-PVP have been reported previously,32 hence the data are not shown.

Figure 9. Normalized IR spectra of IDM-HPMC films at different drug loadings. Percentages in the legend refer to the drug loading. DSC Measurements. The glass transition temperatures of the bulk ASDs were determined using DSC, and the results are shown in Figure 10. Typically, a miscible drug-polymer system shows a single, concentration dependent Tg, while a phase separated drug-polymer system would be expected to show two Tgs that are relatively invariant with respect to composition.33, 34 In the current study, only one Tg was observed for each sample. However, the Tgs of IDM-HPMC ASDs with drug loadings in the range of 90%~50% were essentially composition independent and close to the Tg observed for pure amorphous indomethacin. The absence of a second Tg 12 ACS Paragon Plus Environment

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might result from mixing of the phase separated domains during heating, which has been observed for other compounds.25, 35 For higher polymer concentrations (40%~10% drug loading), the IDM-HPMC ASDs showed a significant increase in Tg with increased polymer concentration, indicating that these samples were miscible. While not definitive, the DSC results support other experimental observations that the miscibility limit of IDM in HPMC is around 50% drug loading. For the IDM-HPMCAS system, it was found that the Tgs of the ASDs showed a slight variation for samples with drug loadings in the range of 90%~30%, and then increased sharply towards the polymer Tg for drug loadings of less than 30%. Again, the DSC data support the supposition that the miscibility limit of IDM in HPMCAS is approximately 30%. For the IDM-PVP system, the Tgs of ASDs increased linearly with increasing polymer concentration across the entire composition range.

Figure 10. Tgs of IDM-HPMC, IDM-HPMCAS and IDM-PVP bulk ASDs as a function of drug loading (mean values, n=2).

IDM-Polymer Physical Stability X-ray Diffraction. The ASDs of IDM with different polymers were prepared and stored at 40 °C. XRD measurements were performed at different times to monitor sample crystallization. The XRD results obtained from IDM-HPMC, IDM-HPMCAS and IDM-PVP ASDs with different drug loadings are shown in Figure 11, 12 and 13 respectively. For the IDM-HPMC 13 ACS Paragon Plus Environment


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dispersions, samples with drug loadings in the range of 10% to 50% maintained their amorphous state over the experimental period (14 months). However, for samples with drug loadings in the range of 60% and 90%, Bragg peaks were observed after 15 days of storage for the 60% drug loading ASD and after 6 days for the other samples, indicating the occurrence of crystallization. For the IDM-HPMCAS system, samples with drug loadings between 10% and 30% remained Xray amorphous for the duration of studies (13 months). For samples with drug loadings between 40% and 90%, Bragg peaks were observed following storage periods of 10 days or less, indicating that indomethacin had crystallized in these samples. Table 1 summarizes the crystallization onset of the IDM-HPMC and IDM-HPMCAS ASDs, and the results demonstrate that the IDM-HPMC ASDs have better physical stability compared with the IDM-HPMCAS ASDs. For the IDM-PVP ASDs, all samples remained amorphous over the experimental period (3 months). Thus none of the PVP ASDs showed crystallization over the short time periods observed for the ASDs formulated with the cellulose derivatives, suggesting that IDM-PVP ASDs may have the best physical stability, in particular at high drug loadings.


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Figure 11. XRD diffractograms of IDM-HPMC ASDs stored at 40 °C for different times. Percentages refer to the drug loading.

Figure 12. XRD diffractograms of IDM-HPMCAS ASDs stored at 40 °C for different times. Percentages refer to the drug loading.



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Figure 13. XRD diffractograms of IDM-PVP ASDs stored at 40 °C for different times. Percentages refer to the drug loading. Table 1. Crystallization onset of IDM-HPMC and IDM-HPMCAS ASDs stored at 40 °C Drug loading (%)

10

20

30

40

50

60

70

80

90

IDM-HPMC (day)

a

a

a

a

a

15

6

6

6

IDM-HPMCAS (day)

a

a

a

10

6

8

4

2

4

a: amorphous Fluorescence Imaging. The films of IDM-polymer were prepared and stored at 40 °C. Fluorescence imaging was performed at different times to evaluate their physical stability. The fluorescence images of IDM-HPMC, IDM-HPMCAS and IDM-PVP films with different drug loadings at different times are shown in Figure 14, 15 and 16 respectively. Drug crystals were not observed for samples with a drug loading between 10% and 40% for either IDM-HPMC or IDM-HPMCAS films. For samples with higher drug loadings, drug crystals were observed for all samples of both IDM-HPMC and IDM-HPMCAS films. However, the crystallization of IDM16 ACS Paragon Plus Environment

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HPMCAS films occurred earlier and more crystals could be observed as compared to for IDMHPMC films, consistent with the XRD results. For the IDM-PVP films, crystallization was not observed for samples with a drug loading between 5% and 70%, which shows the best physical stability among three systems. Crystals were observed at higher drug loadings after longer time periods (30 days). Fluorescence microscopy may be more sensitive to small levels of crystallinity relative to XRD, in particular to the presence of crystals that form preferentially at the surface of the thin films,36 accounting for discrepancy between the X-ray and fluorescence measurements for this system.

Figure 14. Fluorescence images of IDM-HPMC films stored at 40 °C for different times. Percentages refer to the drug loading.



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Figure 15. Fluorescence images of IDM-HPMCAS films stored at 40 °C for different times. Percentages refer to the drug loading.


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Figure 16. Fluorescence images of IDM-PVP films stored at 40 °C for different times. Percentages refer to the drug loading.

Discussion Miscibility of IDM-Polymer. A miscible ASD can be described as a homogeneous single amorphous phase in which drug and polymer molecules are mixed intimately at a molecular level.19 Miscible dispersions can maintain the drug in amorphous form due to the kinetic inhibition of crystallization by the polymer, although the system is metastable since the crystalline form is more thermodynamically stable and hence there is a thermodynamic driving force for phase transformation. However, if amorphous phase separation occurs or the system is inhomogeneous due to the manufacturing process, crystallization would be anticipated to occur more readily, due to the formation of a drug-rich phase with a lower concentration of polymer, and hence less effective crystallization inhibition. Hence miscibility/homogeneity is considered a 19 ACS Paragon Plus Environment


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desirable property of an ASD formulation. Miscibility can be considered as the solubility of the amorphous drug in a given amorphous polymer and it defines the maximum drug loading where a homogeneous amorphous system can be guaranteed.7 Miscibility is an important consideration during ASD formulation design and a variety of techniques have been employed to evaluate drug-polymer miscibility.16 In this study, fluorescence-based methods were used to evaluate the miscibility of IDM-HPMC, IDM-HPMCAS and IDM-PVP systems. Fluorescence spectroscopy, which is a cornerstone technique in many fields, is an emerging technique for the characterization of amorphous solid dispersions, both in the solid state and in solution. In much of the previous work, environment sensitive fluorescent probes have been added to the system and used to provide information about their microenvironment. However, if a drug is autofluorescent, and the emission spectrum is sensitive to the local environment, it may be possible to monitor the phase behavior without adding probes. For example, it was found that the emission spectrum of the autofluorescent molecule, felodipine, changes in aqueous solution when the drug concentration exceeds the amorphous solubility, and drug-rich nanodroplets are formed. In this instance, the fluorescence intensity increases, and the emission peak undergoes a blue shift when drug aggregates are formed.37 In the current study, we are interested in the local indomethacin environment in a solid dispersion when mixed with different polymers. Previous studies with an environment-sensitive fluorescent probe demonstrated that the probe registered a more hydrophilic environment when dispersed in pure polymer, a more hydrophobic environment when dispersed in pure amorphous drug, and an intermediate environment when the drug and polymer were miscible whereby the hydrophilicity of the environment registered by the probe varied in a fairly continuous manner as a function of the drug loading.12 Indomethacin is fluorescent due to the presence of a tryptophan ring (Figure 1) and therefore can be potentially used as an environment-sensitive probe. If the drug-polymer system is miscible over the entire composition range, the expectation is that the drug emission spectrum would show a change from a more hydrophilic environment (low concentration of drug dispersed in polymer) to a more hydrophobic environment (high concentration of drug in polymer) as the drug molecules change from being surrounded predominantly by polymer to being surrounded predominantly by other drug molecules. However, if phase separation occurs, more abrupt changes in the emission spectrum would be anticipated. As shown in Figure 3-5, at low drug loadings, minor variations in the emission spectrum of IDM are observed as the polymer concentration changes, however in 20 ACS Paragon Plus Environment

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general, the emission spectrum is very different from that seen for pure amorphous IDM (Figure 2). At a certain drug loading, which depends on the polymer used to form the ASD, a new peak emerges at around 480 nm; this peak is seen in the emission spectrum of pure amorphous IDM. Thus the emission spectra at higher drug loadings appear to have contributions from IDM molecules in two environments; in a polymer matrix and in an IDM-rich environment. The fluorescence images shown in Figures 6-8 are broadly in agreement with the spectral data, showing the apparent localization of IDM molecules to show domains with a higher fluorescence intensity at high drug loadings. As summarized in Table 2, good alignment is seen between the various techniques in terms of the drug loading where the various ASD systems appear to form a drug-rich phase. Thus fluorescence spectroscopy and imaging appear to be useful techniques to investigate the phase behavior in ASDs of drugs which exhibit autofluorescence. Table 2. Miscibility of IDM-HPMC and IDM-HPMCAS determined using different methods Miscibility Methods IDM-HPMC

IDM-HPMCAS

IDM-PVP

DSC

40%~50%

20%~30%

all ratios

IR spectroscopy

~50%

-

~80%

Fluorescence imaging

~50%

~20%

~70%

Fluorescence spectroscopy

50%~60%

20%~30%

70%~80%

Comparison with Other Studies. When evaluating miscibility of ASDs, the domain size of phase separation should be considered in the context of the analytical approach being applied. As with all conventional microscopy imaging methods (such as optical light microscopy, IR, Raman spectroscopic mapping etc.), the ability of the fluorescence imaging technique described herein to resolve small domains is diffraction-limited. Hence domains smaller than around 300-500 nm cannot be resolved with this method. In contrast, the fluorescence spectra reflect the local environment of the indomethacin molecules and the formation of domains is being inferred from abrupt changes in the spectra. Therefore, this approach is potentially sensitive to the formation of very small domains in which the local environment of IDM has changed. The molecular origin of the observed changes in the film spectra have not been elucidated to date, but could be due to an increased extent of indomethacin dimer formation, or other indomethacin-indomethacin intermolecular interactions, concurrent with the formation of a drug-rich phase. The IDM-PVP 21 ACS Paragon Plus Environment


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system has been extensively studied with other techniques and it has been established that PVP causes disruption of IDM dimers, forming drug-polymer hydrogen bond interactions.32,

38

Furthermore, the miscibility of this system has been studied with ssNMR using 1H T1ρ relaxation measurements.38 IDM-PVP ASDs were found to be miscible at a domain size of ~5 nm based on the 1H T1ρ relaxation measurements, for ASDs containing 10-50 wt.% polymer. Miscibility was also inferred from the IR studies given the observed formation of drug-polymer hydrogen bonds. Our results are in broad agreement with previous experiments, showing a high degree of miscibility between PVP and IDM, with the exception of the high drug loading systems where phase separation is suggested by the fluorescence spectra and images. One possible explanation for the discrepancy at high drug loadings is the difference in the ASD preparation method between the various studies. Previous studies have shown the miscibility can be impacted by solvent composition39 as well as preparation technique.30 Another explanation might be that the fluorescence emission spectra are highly sensitive to the formation of IDM dimers, and that dimer formation is responsible for the emergence of the new peak at ~480 nm. In this scenario, the fluorescence spectra are reporting on the balance between drug-polymer and drug-drug interactions which vary as a function of composition. However, this does not explain the observed heterogeneity in the uniformity of the fluorescence seen in the images presented in Figure 8. Clearly more investigations are warranted to better understand the origin of the variations in IDM emission spectra as a function of polymer composition. Correlation between Miscibility and Stability. It has been suggested that miscible ASDs should have better physical stability than the immiscible ASDs.7,

31

However, studies of the

correlation between miscibility and ASDs stability are limited. Rumondor et al. studied the crystallization kinetics of various felodipine ASDs and suggested that the very rapid crystallization seen for systems containing PVP and stored at high relative humidity (RH) could be accounted for moisture-induced phase separation.40 Paudel and Van den Mooter prepared naproxen-PVP dispersions from different solvents via spray drying and noted differences in miscibility and in the corresponding physical stability of the systems following storage at high RH.41 In the current study, physical stability was assessed without the complicating influence of absorbed moisture, which can impact the miscibility, allowing a direct correlation between miscibility and physical stability to be probed. Figure 17 illustrates that ASD systems that were determined to be miscible have excellent stability to crystallization, whereas those in which a 22 ACS Paragon Plus Environment

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drug-rich phase was detected, undergo crystallization at short time periods. These observations are particularly important for the HPMCAS and HPMC (to some extent) dispersions where the evolution of an IDM-rich phase occurred at drug loadings of relevance for commercial ASD formulations (20-30 and 50-60% drug loading for HPMCAS and HPMC systems respectively). The observed correlation between miscibility and robustness to crystallization highlights the need to evaluate the homogeneity of different formulations during formulation screening.

Figure 17. Relationship between miscibility and crystallization onset of IDM-HPMC and IDMHPMCAS systems.

Conclusion Fluorescence-based methods provide new approaches to probe the local environment of autofluorescent drugs in amorphous solid dispersions and hence investigate miscibility, phase separation and their correlation to ASD performance. Herein, it was found that indomethacin was only miscible at relatively low drug loadings when formulated with HPMCAS, whereas the miscibility increased when mixed with HPMC. Indomethacin-PVP dispersions exhibited the largest miscibility range. The formation of drug-rich domains when the miscibility limit of indomethacin was exceeded led to an enhanced susceptibility to crystallization, whereas homogeneous dispersions were stable to crystallization for long periods of time. This study reinforces the importance of formulating homogeneous drug-polymer dispersions in order to ensure that robust ASDs, that are resistant to crystallization during storage, are produced.



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Acknowledgements This work was partially funded by the China Scholarship Council (File No. 20148210116). The authors also acknowledge the U.S. Food and Drug Administration for financial support under grant award 1U01FD005259-01.

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Investigating the Correlation between Miscibility and Physical Stability

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