Selective Acceleration of Crystal Growth of Indomethacin Polymorphs

Subscriber access provided by READING UNIV

Article

Selective Acceleration of Crystal Growth of Indomethacin Polymorphs by Low-Concentration Poly(ethylene oxide) Qin Shi, Jie Zhang, Chen Zhang, Jing Jiang, Jun Tao, Dongshan Zhou, and Ting Cai Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00854 • Publication Date (Web): 10 Nov 2017 Downloaded from http://pubs.acs.org on November 16, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Molecular Pharmaceutics is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 31

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

Molecular Pharmaceutics

Selective Acceleration of Crystal Growth of Indomethacin Polymorphs by Low-Concentration Poly (ethylene oxide) Qin Shi†, Jie Zhang†, Chen Zhang§, Jing Jiang§, Jun Tao†, Dongshan Zhou§, Ting Cai*,†, ‡ †State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China ‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China §Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China

Abstract: Physical stability of pharmaceutical amorphous solid dispersions is one of the critical attributes to the successful development of the formulation. Herein, we studied the impact of low-concentration poly(ethylene oxide) (PEO) on the crystallization rates of three polymorphs of indomethacin (IMC, γ, α and δ-form). We observed that the addition of 3% w/w PEO significantly increased the crystal growth rates of γ-form and α-from of IMC, but had a negligible effect on the δ-form. The reduction of the activation energy for the crystal growth of IMC polymorphs after adding the PEO follows the order γ-form > α-form > δ-form, which is consistent with the trend toward the accelerating effects of PEO on the crystal growth rates of three polymorphs. With the addition of low-concentration PEO, there is an increase of molecular mobility of IMC as evidenced by the decreased structural relaxation times and viscosities. This study suggests that the substantially different effects of PEO on the crystal growth rates of IMC polymorphs are attributed to the different adsorption of PEO on the crystal surface of those polymorphs, which in turn exerts a selective accelerating effect on IMC molecules to organize into the different crystalline phases. These findings are relevant for understanding the crystallization behavior of amorphous solid dispersions containing polymorphic drugs. ACS Paragon Plus Environment


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

Keywords: indomethacin; polymorphism; poly (ethylene oxide); crystal growth; molecular mobility

Introduction The solid state properties of active pharmaceutical ingredients may significantly impact physicochemical, mechanical, and biopharmaceutical performances of oral solid dosage forms.1-3 In recent years, there are an increasing number of new drug candidates suffering from low aqueous solubility that limit their in vivo dissolutions and thus their bioavailability. The aqueous solubility of amorphous form of a molecule is typically higher than its crystalline counterpart because little or no energy is required to break up the crystal lattice during the dissolution process.4-7 Use of the amorphous form of a drug has become one of the most effective formulation approaches to enhance the oral bioavailability of poorly water-soluble drugs.8-9 Since the amorphous form is thermodynamically unstable relative to the crystalline form, one of main challenges in developing amorphous formulations is maintaining the amorphous nature and solubility advantages in the long term. It has been reported in several studies that some polymeric carriers, such as poly(vinyl pyrrolidone) (PVP) and cellulose derivatives can effectively inhibit the crystallization of amorphous drugs in the solid state.10-16 In general, the addition of polymeric antiplasticizer with a high glass transition temperature (Tg) can decrease the molecular mobility of the amorphous drug, thus reduce the crystallization tendency.17-18 In addition, the formations of specific interactions between the drug and polymer are also well accepted as important factors governing the physical stability of amorphous pharmaceutical solids. For instance, Kestur and Taylor assessed the inhibitory effect of several polymers on the crystallization of amorphous felodipine.14 They observed that polymers which formed stronger hydrogen bonds with the drug molecules appeared to be more effective inhibitors of crystal growth.14 Recently, Suryanarayanan and coworkers demonstrated that the extent ACS Paragon Plus Environment

Page 2 of 31

Page 3 of 31

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


of inhibition was dependent on the strength of the drug-polymer hydrogen bonding and the structural relaxation times which were characterized by dielectric spectroscopy.12,19,20 Stronger drug-polymer hydrogen bonding interactions yield more reduction in molecular mobility and hence provide greater resistance to crystallization.12,19-20 Interestingly, it has been reported that even at very low-concentration, some polymers with low Tg can significantly accelerate the crystallizations of amorphous drugs.13,

21-23

For example, the crystal growth rates of amorphous griseofulvin (GSF)

increase significantly by two orders of magnitude in the presence of 3% w/w Poly (ethylene oxide) (PEO).22 This accelerating effect can be attributed to not only the increase of global mobility as evidenced by the reduction of α-relaxation times, but also the high segmental mobility of PEO.22 Although many efforts have been made to understand the effects of polymer on the crystallization of amorphous solid dispersions, it remains unclear whether or not polymers exhibit the same power on altering the crystallization rates of different polymorphs of a drug. Kestur et al. found that the inhibitory effect of PVP on the crystal growth rates of two felodipine polymorphs appeared to be similar.24 However, recently Zhang et al. reported that the From II of itraconazole was much more sensitive than Form I to the growth inhibition by Kollidone VA64 and hydroxypropylmethyl cellulose acetate succinate.25 Indomethacin (IMC), a popular anti-inflammatory drug, often serves as a model system for studying the physical stability of amorphous pharmaceutical solids. Herein, we studied the impact of low-concentration PEO on the crystallization rates of three polymorphs of IMC (γ, α and δ-form). We observed that the addition of 3% w/w PEO significantly increased the crystal growth of γ-form and α-from of IMC, but it had a negligible effect on δ-form. In order to understand this phenomenon, the changes of the activation energy of crystal growth, and the coupling between liquid dynamics and crystallization kinetics upon doping with low-concentration PEO were investigated for three different polymorphs. This study suggests that the substantially different effects of PEO on the crystal growth rates of IMC polymorphs could be attributed to the different adsorption ACS Paragon Plus Environment


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

of PEO on the crystal surface of those polymorphs, which in turn exerts a selective accelerating effect on IMC molecules to organize into the different crystalline phases.

Experimental section Materials Indomethacin (1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-aceticacid,99+%, γ polymorph, Tg =314K) and Poly(ethylene oxide) (PEO, Mv=100000, Tg=226K) were purchased from Sigma-Aldrich (St. Louis, MO, USA) and used as received.

Indomethacin

Poly (ethylene oxide)

Preparation of PEO/IMC Mixtures Mixtures of IMC and PEO were prepared by cryogenic milling (SPEX SamplePrep 6770 Freezer/Mill, USA), a procedure found to be effective for making uniform drug-polymer mixtures. Typically, 1 g of IMC and PEO powder blend was cryomilled at 10 Hz for five cycles using liquid nitrogen as a coolant. Each cycle of milling time was 2 min, followed by a 2 min cool-down process. To ensure uniform mixing of IMC and low-concentration PEO, a two-step dilution was applied. A 10% w/w PEO dispersion in IMC was first prepared and then diluted to make 3% w/w PEO-doped IMC mixtures. Thermal Analysis Differential scanning calorimetry (DSC) was performed with a TA instrument DSC Q2000 (New Castle, DE, USA) equipped with a refrigerated cooling accessory (RCS 90, TA instrument, New Castle, DE, USA) under 50 mL/min N2 purge. The annealing method, which has been reported by Yu et al., 26 was applied for obtaining the solubility of IMC crystals in PEO. 10~15 mg of cryomilled ACS Paragon Plus Environment

Page 4 of 31

Page 5 of 31

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


IMC/PEO (10/90,30/70,50/50,70/30, all in w/w ratio) mixtures were sealed hermetically in aluminum pans and annealed at a desired temperature for 4 h then scanned at a heating rate of 10 K/min to determine if the residual IMC crystals were completely dissolved. Compared to the regular scanning method,27-28 the annealing method yields more accurate data by facilitating the attainment of phase equilibrium. Fourier transform infrared (FT-IR) spectroscopy FT-IR spectroscopy (Thermo Fisher, Nicolet iS10, Madison, USA) was used to investigate the specific interactions between IMC and PEO. Samples of pure IMC and cryomilled IMC/PEO (30/70, 50/50, 70/30, all in w/w ratio) mixtures were completely melt at 458K and subsequently quenched to become amorphous mixtures by liquid nitrogen. Before FT-IR analysis, each sample was dispersed uniformly in KBr and then compressed into a disc. 64 scans were collected for each sample over the wavenumber range of 4000-400cm-1 with a resolution of 4cm-1. Raman microscopy Raman Microscopy (ThermoFisher DXR, Madison, USA) equipped with a 780 nm externally stabilized diode laser was used to identify the polymorphism of IMC. Raman spectra were recorded over the wavelength range of 3350-50cm-1 with a resolution of 1 cm-1 and an exposure time of 2 secconds, 30 times, using a laser power of 24 mW. OMNIC software was used to analyze the Raman spectra. Broadband dielectric spectroscopy (BDS) Dielectric measurements were performed in a temperature range of 315-369 K for pure IMC and binary IMC-PEO samples using a Novocontrol Alpha dielectric spectrometer (Concept80, Novocontrol Technologies, GmbH& Co. KG, Germany) over a frequency range of 10−2−106 Hz at atmospheric pressure. The samples prepared by melt-quenching were packed tightly between two cooper coated brass electrodes (20mm diameter) enclosed by a PTFE ring spacer (area of 59.69 mm2 ACS Paragon Plus Environment


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

Page 6 of 31

and thickness of 0.5 mm). Novo-Control Quattro system was used to control the temperature with stability better than 0.01 K. To avoid overflowing to the edge of electrodes, liquid samples were confined in the center of the gold plate copper electrodes by a circular spacer. To obtain the average relaxation time (τHN) and shape parameters (α and β), the experimental data have been fitted using Havrililak-Negami (HN) type dielectric function plus dc-conductivity term:

∗ = ′ − = ∞ +

+

α β

σ

ε

(1)

where ε*(ω) represents the complex dielectric permittivity consisting of dielectric constant (ε′) and dielectric loss factor (ε″), ε∞ is high frequency limit permittivity and ∆ε = εs- ε∞ is dielectric strength with εs being the static dielectric constant. ω is the angular frequency, τHN is the average relaxation time determined by HN equation and the exponents α and β (0 < α, αβ ≤ 1) represent asymmetry and width of the relaxation peak, respectively. With increasing temperature, an increased contribution of conductivity was observed in the low frequency region of dielectric spectra. This was taken into consideration by including the conductivity component, σdc/iε0ω to the HN equation, where the value of σdc quantifies the level of dc-conductivity and ε0 denotes the permittivity of vacuum. Edge compensation, stray capacitance and spacer capacitance were all corrected in dielectric measurements. On the basis of fitting parameters determined by HN functions in eq 1, the values of α-relaxation time are calculated as: %

/

= = !sin &&'(

%'

/

!sin &&'(

(2)

Temperature dependences of α-relaxation time in supercooled liquids are most frequently described using the empirical Vogel−Fulcher−Tammann (VFT) equation. /0

= * exp .00 1

(3)

In the VFT equation, τ is the average α-relaxation time, τ0 is the relaxation time of the unrestricted material (10-14 s, the quasi lattice vibration period), T0 is the zero mobility temperature and D is the ACS Paragon Plus Environment

Page 7 of 31

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


strength parameter for a measure of fragility. As discussed later, we observed secondary relaxation peaks in pure IMC and IMC-PEO binary system. Compared to the primary relaxation (α-relaxation), secondary relaxations represent the non-cooperative motion, which are characterized by shorter relaxation times and relatively lower activation energies. The temperature dependences of secondary relaxation are commonly fitted to the Arrhenius equation as follows:

= * exp .

△3 40

1

(4)

where, △E is the activation energy for secondary relaxation and R is the universal gas constant. Shear Viscosity Measurement The steady shear viscosity of amorphous IMC and binary IMC-PEO systems were measured using an ARES G2 rheometer (TA Instruments, New Castle, DE, USA). Measurements were conducted using two 25 mm-diameter parallel plates with a 0.4 mm gap size between them. Nitrogen gas was used to control the temperature inside the heating hood. Briefly, IMC crystalline powders were melted onto the lower parallel plate at 438 K (5 K higher than the melting point of γ-IMC) for 5-10 minutes to ensure complete melting. The upper plate was then lowered, and excess material was trimmed off along the border of the plates. After that, the temperature was lowered to a desired temperature (343 K, 353 K, 363 K or 373 K). Before shear treatment, the samples were equilibrated at the experimental temperature for 15min. Then, a shear deformation was applied at a rate of 0.1s-1 to 10s-1 at a constant temperature. The values of shear viscosity were recorded when the shear rate reading become steady. Responses were obtained in term of viscosity (Pa﹒s) versus temperature (K). Bulk crystal growth of IMC in the presence of PEO The crystal growth was tracked by using a polarized light microscope (Olympus BX53 microscopy equipped with an Olympus Digital Camera DP26, Tokyo, Japan) equipped with a hot stage ( Linkam THMS 600, Surrey, U.K.) to achieve the temperature control. Briefly, 3-5 mg of crystalline IMC or ACS Paragon Plus Environment


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

cryomilled IMC/PEO mixtures were melt between two clean coverslips at 438K for 3 min and subsequently quenched to room temperature to form a clear amorphous film. Under the cross-polarized microscope, these samples were confirmed to be amorphous by the absence of birefringence. The thickness of the liquid sandwiched between two cover slips was 15~20 µm. To study the crystal growth of δ-form of IMC, the melt-quenched samples were placed on a hot stage maintained at a desired temperature and δ-form crystallized spontaneously in the bulk. The growth rate of δ IMC was measured with spontaneously nucleated crystals. Since the spontaneous nucleation of δ-form of IMC was fast and preferred in the melt from 343 to 373 K, the growth rates of α and γ polymorph were measured with crystals initiated by either spontaneous nucleation or seeding.29 The seeding experiments were done by pushing crystals of α-IMC or γ-IMC into contact with the supercooled liquid to initiate the growth at 373K, and then transferred to a desired temperature for measuring the crystal growth rates. The seeds of γ polymorph were obtained directly from the purchased IMC raw materials. The seeds of α polymorph were crystallized from an ethanol solution upon adding water. The polymorphism of IMC crystals grown in the melt was identified by Raman microscopy. Crystal growth rates measured from spontaneously nucleated or seeded crystals were observed to show no significant difference. We measured the growth rate by tracking the advancing speed of a crystal front into the supercooled liquid. The crystal growth rates were independent of time during the measurement. Each reported growth rate was the average of several measurements with three independently prepared samples.

Results State of mixing and drug-polymer molecular interactions

ACS Paragon Plus Environment

Page 8 of 31

Page 9 of 31

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


Figure 1. FT-IR spectra of amorphous IMC containing different concentrations of PEO (0%, 30%, 50%, 70% w/w)

The miscibility between drug and polymer will affect the crystal growth of amorphous solid dispersions. IMC can serve as both hydrogen bond donor and acceptor. It has been reported by several research groups that IMC is capable of hydrogen bonding with various polymers in amorphous solid dispersions.30-31 Figure 1 shows the FT-IR spectra of various IMC/PEO solid dispersions in the carbonyl stretching region (1850-1500 cm-1). The Spectrum of pure amorphous IMC is comprised of benzoyl carbonyl vibration (1680 cm-1), asymmetric acid carbonyl vibration of cyclic dimers (1710 cm-1) and non-hydrogen bonded acid carbonyl stretch vibration (1735 cm-1).32 With the addition of PEO, the peak assigned to the asymmetric stretch of carboxylic acid in a dimer structure of IMC shifts to 1730 cm-1, suggesting that PEO interferes through hydrogen bonding with the dimer formation in amorphous IMC. Similar results were observed in the FT-IR study of IMC-PVP system, where PVP disrupted the self-interaction of amorphous IMC and interacted with IMC through hydrogen bonding.30



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

Page 10 of 31

Figure 2. Activity of IMC a versus PEO weight fraction w. The red solid line represents the Flory-Huggins fit.

To further determine the miscibility between PEO and IMC, we calculate the Flory-Huggins interaction parameter of this binary system based on the solubility data of crystalline IMC in PEO obtained from DSC measurements.26 The drug's activity a, a measure of drug solubility in a saturated polymer solution, can be calculated by the following equation: ln a=(∆Hm/R)(1/Tm - 1/T)

(5)

where ∆Hm and Tm represent the enthalpy and melting temperature of the pure drug, respectively. T is the temperature at which the drug's solubility is measured, equivalent to its depressed melting point. As shown in Figure 2, the activity of IMC decreases significantly with increasing the PEO content. According to the Flory−Huggins model, the activities of IMC calculated by eq 5 are fitted by the following equation: lna=lnvdrug+(1-1/x)vpolymer+χvpolymer2

(6)

where vdrug and vpolymer represent the volume fraction of IMC and PEO, respectively. x is simplified to the ratio of the molecular weight of PEO and IMC assuming the volume fraction is the same as the weight fraction. χ is the drug-polymer Flory-Huggins parameter, which can be used to assess the miscibility and interaction between the drug and polymer. The red curve in Figure 2 describes the fitting of IMC activities to the Flory-Huggins model. The χ value obtained for IMC-PEO system is -2.76. Compared to the other binary systems of drug-PEO,22,33 the relatively large negative value of ACS Paragon Plus Environment

Page 11 of 31

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


Flory-Huggins parameter for IMC-PEO describes the existence of strong molecular interactions between IMC and PEO in solid dispersions, which favors miscibility. This result is also consistent with the aforementioned study on FT-IR spectroscopy. Crystal growth morphologies and kinetics of amorphous IMC doped with or without the low-concentration PEO

Figure 3. Polarized optical microscope images of γ，α and δ-IMC crystals grown at 373K in the presence and absence of PEO.

As a model system for studying the physical stability of amorphous drugs, IMC has been reported to crystallize into γ, α and δ-form in its supercooled liquid.29 Figure 3 shows the images of IMC crystals（γ，α and δ-form）grown at 373 K (Tg + 59 K) in the presence and absence of 3% w/w PEO. Both γ and α-IMC grow consistently as polycrystalline spherulites with the smooth crystal/liquid interface. While the morphology of δ-IMC crystals shows individual fibers at growth front protruded into the amorphous region. There were no significant changes in the growth morphologies of γ，α and δ-form of IMC with the addition of low-concentration PEO (Figure 3). Raman microscopy is used to distinguish and identify the polymorphs of IMC grown in the presence and absence of PEO. Figure 4 shows the Raman spectra of IMC polymorphs, which are in agreement with those reported by Wu et al.29 The Raman spectrum of δ-IMC shows two vibrations at 1688 and 1676 cm-1, corresponding to ACS Paragon Plus Environment


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

the stretches of carbonyl groups. For the Raman spectrum of α polymorph, the peak at 1692 cm-1 is assigned to the carbonyl stretch of benzoyl group, and the peaks at 1680 and 1649 cm-1 are attributed to the carbonyl stretch of carboxylic acid.30 Compared to the Raman spectra of δ and α polymorph, γ-IMC shows one carbonyl stretching vibration at 1698 cm-1 due to the formation of cyclic dimer.30 No significant changes can be observed in the Raman spectra of IMC polymorphs grown in the presence of 3% w/w PEO. In Figure 5a and 5b, the addition of 3% w/w PEO dramatically accelerates the crystal growth of α and γ-IMC over the temperature range from 343 K to 373 K. Notably, at 343 K, the addition of 3% w/w PEO increase the crystal growth rates of α and γ forms of IMC by approximately 20- and 50-fold, respectively. These accelerating effects of PEO on crystal growth rates of α-IMC and γ-IMC gradually diminish at elevated temperatures (e.g. 373 K). However, much to our surprise, the crystal growth rates of δ-form of IMC are barely increased in the presence of 3% w/w PEO within a temperature range of 343 K to 373 K.

Figure 4. Raman spectra of IMC polymorphs with or without 3% w/w PEO


Page 12 of 31

Page 13 of 31

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


Figure 5. Crystal growth kinetics of IMC (a) γ-form; (b) α-form; (c) δ-form with or without 3% w/w PEO as a function of temperature.

Liquid dynamics of IMC in the presence and absence of low-concentration PEO Molecular mobility

Figure 6. Dielectric loss spectra for (a) pure IMC and (b) IMC-PEO (3% w/w)

The dielectric spectroscopy enables us to investigate the molecular mobility of amorphous IMC in the presence and absence of PEO additives. As shown in Figure 6a, dielectric loss spectra of pure IMC in the supercooled liquid state from 315 to 369 K reveal well-resolved peaks that are attributed to α-relaxation, a measure of global molecular mobility. The α-relaxation peaks progressively shift to higher frequencies with increasing the temperature, indicating that the global molecular motions become faster. In the vicinity of the Tg of IMC, a weak relaxation peak is also observed, which corresponds to a secondary relaxation (local molecular mobility). It is well known that secondary relaxations can originate from local motions of different nature. In the case of IMC, two secondary ACS Paragon Plus Environment


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

relaxation processes have been reported.34,35 The slower one is the Johari-Goldstein β–relaxation, which is regarded as a precursor of α-relaxation and almost invisible in the dielectric spectra at ambient condition.34 The faster one is the γ-relaxation, reflecting the rotation of the chlorobenzyl groups of IMC molecules.35 In our measurements, the γ-relaxation peaks became visible when the temperature was close to the Tg of IMC. In Figure 6b, dc-conductivity signals increase significantly in the samples doped with 3% w/w PEO. In our previous study, a dramatically increase of dc-conductivity signals are also observed in the amorphous griseofulvin doped with small amounts of PEO.22 No significant decrease in the magnitude of the dielectric loss peak is found in the spectra, suggesting no obvious crystallization occurs during the dielectric measurements.

Figure 7. Dielectric loss behavior of pure IMC and IMC-PEO (3% w/w) at 327 K.

As shown in Figure 7, in the presence of 3% w/w PEO, the α-relaxation peak of IMC at 327 K moves to higher frequencies, which indicates a pronounced increase in molecular mobility. Figure 8 reveals the temperature dependence of α-relaxation times for amorphous IMC in the presence or absence of 3% w/w PEO in the supercooled liquid state. The nonlinear temperature dependences of α-relaxation times can be described by the empirical VFT equation (eq. 3) while γ-relaxation times generally obey an Arrhenius temperature dependence (eq. 4). It is worth noting that the addition of low-concentration PEO yields a progressive decrease on the α-relaxation times as a function of ACS Paragon Plus Environment

Page 14 of 31

Page 15 of 31

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


temperature and this effect becomes more pronounced at large supercoolings. The presence of PEO also decreases γ-relaxation times significantly, indicating the enhancement of the local mobility as well.

Figure 8. Temperature dependence of the α-relaxation and γ-relaxation time for pure IMC and IMC-PEO (3% w/w).

Viscosity

Figure 9. Zero-shear viscosity of pure IMC and IMC-PEO (3% w/w) as a function of temperature.

The steady shear viscosities of pure IMC and IMC doped with 3% w/w PEO are measured in a temperature range of 343-373 K. As shown in Figure 9, the addition of low-concentration PEO significantly decreases the viscosity of IMC. At 343 K, the decrease in viscosity of IMC liquid by PEO is approximately 6-fold. Analogous to the α-relaxation times, the degree of reduction in the viscosity of amorphous IMC by PEO shows temperature dependence as well, being less pronounced ACS Paragon Plus Environment


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

at elevated temperatures.

Discussion Effect of low-concentration PEO on the crystallization kinetics of IMC polymorphs

Figure 10. Ratios of the growth rates of IMC in the presence of 3% PEO to IMC in the absence of polymer for γ-, α- and δ- form at 343, 353, 363 and 373 K. The crystal growth rates are obtained from Figure 5.

It has been demonstrated in a number of studies that low-concentration polymer additives can substantially influence the crystallization rates of small-molecule drugs in the supercooled liquids.36 14,24-25,37-38

Kestur et al. reported that low-concentration PVP significantly reduced the crystal growth

rate of felodipine in the solid state above its Tg.38 The inhibitory effects of PVP were greatly dependent on the polymer concentration and molecular weights.38 A further study with more polymers showed that the inhibitory effects on the crystal growth correlated well with the strength/extent of drug-polymer hydrogen bonding interaction.14 The difference of molecular mobility between a polymer and drug molecule was also found to play an important role in mediating the crystal growth.23 For instance, polyhydroxybutylate is a biocompatible polymer that can act as either a crystal growth inhibitor or accelerator, depending on the Tg of the host drug molecule.23 Recently, we observed that the crystal growth rates of GSF were increased by two orders of magnitude in the presence of 3% w/w PEO.22 In the present work, the accelerating effect of low-concentration PEO on the crystal growth rates of IMC appears to show a strong polymorphic ACS Paragon Plus Environment

Page 16 of 31

Page 17 of 31

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


dependence. The addition of 3% w/w PEO yields approximately 50- and 20-fold increase in the crystal growth rates of γ- and α polymorph of IMC at 343K, but it has a negligible effect on δ-form (Figure 10). Kestur et al. observed that the growth-inhibitory effect of PVP on the felodipine polymorphs were similar.24 They concluded that the inhibitory effect of PVP on the crystal growth of felodipine was mainly attributed to the effect on the amorphous material rather than at the crystal surface.24 Recently, Zhang et al. reported that the polymers differed substantially in their effect on the crystallization kinetics of two polymorphs of itraconazole.25 At 355K, the addition of 20% w/w HPMCAS yielded approximately 18-fold decrease in the crystal growth of itraconazole polymorph II while 6-fold decrease for polymorph I.25 In the present study, it is apparent that PEO exerts a selective acceleratory effect on the crystal growth of IMC polymorphs which follows the order γ-form > α-form > δ-form. The effects of PEO on the crystal growth rates of γ- and α-IMC also exhibit the strong temperature dependence. The addition of 3% w/w PEO significantly accelerates the crystal growth rates of γ- and α-IMC by more than one order of magnitude at 343K, but it has a smaller effect on the crystal growth at 373K. Notably, temperature-dependent effects of polymer on the crystal growth of amorphous drugs have been observed in several studies.14,24,36 Hajime et al. reported that 2% w/w PVP reduced the growth rate of nifedipine by two orders of magnitude nearby the Tg, while it had little effect on the crystal growth at the temperature well above Tg.36 Analogously, the inhibitory effects of polymers on the crystal growth of felodipine also gradually diminished with increasing the temperature.14 The less effectiveness of polymers as crystal growth inhibitors at elevated temperatures were attributed to the decreased strength of hydrogen bonding between the polymer and drug.14 In this case, the acceleratory effects of PEO for γ- and α-IMC decrease with increasing the temperature, which is most likely to be a result of the different temperature dependences of ACS Paragon Plus Environment


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

Page 18 of 31

molecular mobility between PEO and IMC, where the IMC molecules become more mobile relative to PEO upon heating.21 Effect of low-concentration PEO on the activation energy barrier for the crystal growth of IMC polymorphs As shown in Figure 11, the growth kinetics of three polymorphs of IMC with or without low-concentration PEO follows the Arrhenius equation: 3

5 = 6 exp407

(7)

where u is the crystal growth rate, A is the pre-exponential factor, R is the gas constant and Ea is the activation energy associated with the process of crystal growth. As shown in table 1, the calculated activation energies for pure γ，α and δ polymorphs of IMC are 156.98, 175.24 and 140.47 kJ/mol, respectively. Interestingly, in the presence of 3% w/w PEO, the activation energies of γ and α form are significantly decreased, while that of δ form is much less affected. With the addition of PEO, the activation energies for the crystal growth of γ, α and δ polymorph are decreased by 102.49, 80.48 and 2.47 kJ/mol, respectively. The extent of the decrease in kinetic barrier by adding PEO are rank ordered as γ-form > α-form > δ-form, which is consistent with the aforementioned trend toward the acceleratory effects of PEO on the crystal growth of IMC polymorphs. Very recently, Kaminska et al. reported that the addition of acetylated sucrose and acetylated maltose inhibited the crystal growth of amorphous naproxen along with increasing the activation barrier for crystallizations.39 Madejczyk et al. compared the effects of acetylated saccharides on the activation energy barrier for crystal growth of various polymorphic forms of nifedipine.40 They found acetylated saccharides significantly increase the activation energy barrier of crystallization of α-form but not β-form.40


Page 19 of 31

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


Figure 11. Arrhenius kinetics of crystal growth for IMC polymorphs with or without of 3% w/w PEO. Table 1. Activation energy Ea of the crystal growth of IMC polymorph in the presence and absence of 3% w/w PEO

materials

Ea IMC (kJ/mol)

γ-IMC α-IMC δ-IMC

156.98 175.24 140.47

Ea IMC-PEO (3% w/w) (kJ/mol) 54.49 94.76 138.00

△Ea (kJ/mol) 102.49 80.48 2.47

Coupling between liquid dynamics and crystallization kinetics of IMC polymorphs in the presence and absence of PEO

Figure 12. Plots of characteristic crystallization time τu versus α-relaxation timeτa in supercooled IMC polymorph. (a) pure IMC, (b) IMC- PEO (3% w/w).

To investigate the potential relationships between crystallization and molecular mobility, linear correlations can be established by the following equations: log10τcr = ξxlog10X+A

(8) ACS Paragon Plus Environment


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

Page 20 of 31

where τcr represents the crystallization rate or characteristic crystallization time, which can be examined in several manners such as inverse overall crystallization rate, the onset time of crystallization, and characteristic time for a certain degree of crystallization, etc. X represents the measurement of molecular motions such as structural relaxation, secondary relaxation, diffusivity and viscosity, etc. ξx, termed as coupling coefficients, is a measure of the coupling relations for above-mentioned crystallization process and molecular motions.41 A value of ξx ≈ 1 is a strong indicator that the crystallization process can be mainly attributed to the investigated molecular mobility, whereas the smaller value of ξx means the investigated molecular mobility is less responsible for the crystallization. In this study, we consider α-relaxation time and τu as the factors responsible for molecular mobility and crystallization process. τu is defined as the time for the crystal to grow one molecular layer. τu =a/u, where a is the calculated diameter of IMC molecules (~8.5Å)42 and u is the crystal growth rate obtained from Figure 5. The plots of characteristic crystallization time τu versus α-relaxation time τa are linear for three polymorphs of IMC with or without low-concentration PEO (Figure 12). Table 2. Coupling coefficient ξx for structural relaxation time τα and characteristic crystallization time τu.

materials

Pure IMC

IMC-PEO(3% w/w)

γ-IMC

0.65

0.31

α-IMC

0.77

0.62

δ-IMC

0.62

0.78

As shown in Table 2, the coupling coefficient values of γ, α and δ polymorph are 0.65, 0.77, and 0.62, respectively, indicating substantial but not very strong coupling between τα and τu. The addition of 3% w/w PEO alters the coupling coefficients of three IMC polymorphs. It is apparent that the presence of low-concentration PEO can affect the coupling between the molecular mobility and crystallizations, particularly for γ polymorph. Since the IMC monomer can form hydrogen bonding ACS Paragon Plus Environment

Page 21 of 31

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


interactions with PEO,32 the dynamics of dilute PEO are tightly couple to the dynamics of IMC due to the strong drug-polymer interactions.43 In the supercooled liquid of IMC, the presence of PEO effectively increases the molecular mobility of IMC as characterized by dielectric spectroscopy. However, the increase of global mobility by PEO appears to be insufficient to explain the variation of coupling coefficients for three IMC polymorphs. Figure 13 shows the growth rate u as a function of the liquid viscosity in a log-log format, where supercooled liquid IMC is approximately described by a straight line in intermediate and deep supercooled region. Therefore, u can be described to exhibit a power law dependence upon the liquid viscosity: u ∝ η-ξ

(9)

Ediger and co-workers have revealed that the value of ξ depends systematically on the fragility of the liquids44. The fragility m, proposed by Angell et al, is defined as m = d(log η)/d(Tg/T)|Tg, which represents the deviation extents away from an Arrhenius temperature dependence of viscosity.44 In a single component liquid, decoupling between crystal growth kinetic and viscosity essentially represents the decoupling between translational diffusion D and viscosity η, which is strongly related with spatially heterogeneous dynamics.45-47 Briefly, translational diffusion is strongly associated with the fast dynamic, while the viscosity is determined largely by the slowest molecules.48 As shown in Table 3, the effect of PEO on the coupling between viscosity and crystallization kinetics also exhibits a strong polymorphic dependence. The presence of PEO significantly decreases the coupling coefficients of γ- and α-IMC but increases that of δ form. Given that IMC polymorphs crystallize from the same supercooled liquid, spatially heterogeneous dynamics cannot account for the changes on the coupling coefficients for different IMC polymorphs. The growth velocity of a crystal into its melt depends on several important factors, such as the rate of molecule approaching to the crystal surface, the probability of approaching molecule having the ACS Paragon Plus Environment


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

Page 22 of 31

desirable configurations and the probability of that molecule not returning to the liquid phase.44 Here, the effects of PEO on the liquid dynamics (α-relaxation time or viscosity) only reflect the influence on the translational and rotational diffusions.

Figure 13. Log-log plot of crystal growth rate u versus viscosity η (a) γ-IMC; (b) α-IMC; (c) δ-IMC. Table 3. Coupling coefficient ξ for crystal growth rate u and shear steady viscosity η

materials

Pure IMC

IMC-PEO (3% w/w)

γ-IMC

0.66

0.28

α-IMC

0.78

0.50

δ-IMC

0.58

0.74

Relations between polymer adsorptions and selective acceleration on the crystallization kinetics of IMC polymorphs

Figure 14. (a) Plots of α-relaxation times; (b) plots of crystal growth rates as a function of Tg/T.

Figure 14 shows the plots of α-relaxation times and crystal growth rates versus the Tg scaled reverse temperature Tg/T. Here, Tg is dielectric Tg defined as the temperature where τα = 100 s. Once the temperature is scaled by Tg/T, the α-relaxation times of IMC with or without 3% w/w PEO can be perfectly overlapped, indicating that the increase of global mobility is caused by the plasticization ACS Paragon Plus Environment

Page 23 of 31

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


effect.49,50 However, as shown in Figure 14b, the crystallization kinetics of γ and α polymorphs of IMC cannot be overlapped as a function of Tg/T, which suggests that factors other than the liquid dynamics may contribute to the accelerating effects of PEO on the crystal growth of these two polymorphs. For a single component system, the rate of molecules organizing into a crystalline phase from the liquid and the probability of the newly formed crystal irreversibly retained into the crystalline phase contribute to the overall growth rate of a crystal into its melt.44 The former is assumed to be controlled by the self-diffusion while the latter can be expressed by the free energy difference between crystalline and amorphous phase.44 In the presence of polymer, the process of crystal growth becomes more complex. In our previous study, the crystallization kinetics of amorphous GSF containing low-concentration PEO cannot be overlapped with that of pure GSF on the Tg/T scale either.22 Besides the enhanced global mobility, the high segmental mobility of PEO was proposed to accelerate the crystal growth rates of amorphous GSF.22 Furthermore, by examining the effects of polymer additives with different structures and molecular weights, we argued that segmental mobility likely played the role in defining the rate-limiting step for the crystallization, instead of center-of-mass diffusion or intrinsic viscosity of polymer chains.13 However, in the present study, it is apparent that the increase of overall molecular mobility and the high segmental mobility of PEO are still insufficient to explain the discrepant influence on the crystal growth of different IMC polymorphs. As demonstrated in the literature, polymer adsorptions on the crystal surface play an important role in mediating the crystal growth in a supersaturated solution.51-60 Polymer adsorptions can affect the crystal growth by blocking the sites for integration of solute into the lattice, thus inhibiting the crystal growth and even altering morphologies.53-60 For example, Schram et al. observed that hydroxypropyl cellulose acetate succinate (HPMCAS) retarded crystal growth of felodipine by poisoning the crystalline surface, as evidenced by surface characterization with atomic force ACS Paragon Plus Environment


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

microscopy.55 The presence of HPMCAS can also slow down the conversion of the metastable polymorph of nifedipine to its stable polymorph in the solution.61 This inhibition of this polymorphic transformation likely arises from the effect of surface-absorbed polymers on the nucleation and crystal growth of new polymorph.61 In the case of IMC, it appears possible that the adsorption of PEO on the crystal surface of each polymorph can be different during the process of crystallization in the supercooled liquid. It has been found that the specific interactions between additives and certain crystal facets can play an important role in influencing the nucleation processes, crystal habits and growth rates.62,63 Compared to the δ polymorph of IMC, PEO may form stronger interactions with the crystal facets of γ and α polymorph, thus facilitating the polymer absorption on the crystal surface of these two polymorphs. Notably, unlike many polymeric additives which can impede the crystal growth of small molecules by absorption, PEO exhibits the acceleratory effect because of its high segmental mobility.13,21 Since the translational diffusion of small molecules through a polymer matrix is limited by the segmental mobility of polymer chains, with more PEO absorbed at the crystal/liquid interface, the IMC molecules are expected to migrate faster through a PEO-enriched region to reach the crystalline phase, yielding the enhanced crystal growth rate. Therefore, the different absorptions of PEO at the crystal/liquid interface of three IMC polymorphs could influence the rates of IMC molecules transporting through PEO-enriched regions to the different crystalline phases from the supercooled liquid, resulting in a polymorph-dependent effect on the crystal growth rates.

Conclusion In summary, the effects of 3% w/w PEO on the crystal growth kinetics of IMC polymorph (γ, α, δ-form) and liquid dynamics of amorphous IMC have been systematically investigated. We observe that the addition of 3% w/w PEO significantly increases the crystal growth rates of γ-form and α-from of IMC, but has a negligible effect on δ-form. The presence of low-concentration PEO ACS Paragon Plus Environment

Page 24 of 31

Page 25 of 31

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


significantly decreases the viscosity of IMC supercooled liquid and increases the molecular mobility of IMC as well. The reduction of activation energy for the crystal growth rates of IMC polymorphs after adding the PEO follows the order γ-form > α-form > δ-form, which is consistent with the trend toward the accelerating effect of PEO on the crystal growth rates of three polymorphs. The couplings between liquid dynamics and crystallization kinetics of IMC exhibit the strong polymorphic dependence in the presence of PEO. The increase of overall molecular mobility and the high segmental mobility of PEO are insufficient to explain the discrepant influence on the crystal growth of different IMC polymorphs. We hypothesize that the different absorptions of PEO at the crystal/liquid interface of three IMC polymorphs influence the rates of IMC molecules transporting through PEO-enriched regions to different crystalline phases from the supercooled liquid, resulting in a polymorph-dependent effect on the crystal growth rates.

Author Information Corresponding Author

*Address: Department of Pharmaceutics, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Tel: 86-025-83271123. E-mail: [email protected]. Notes The authors declare no competing financial interest.

Acknowledgments The authors are grateful for financial support of this work by the National Natural Science Foundation of China (No. 81402877), the Program of State Key Laboratory of Natural Medicines-China Pharmaceutical University (No. SKLNMZZYQ201604), the Graduate Innovative Research Project of Jiangsu Province (KYLX16_1180), 111 project (B16046) and the Program for ACS Paragon Plus Environment


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

Jiangsu Province Innovative Research Team.

References 1.

Datta, S.; Grant, D. J., Crystal Structures of Drugs: Advances in Determination, Prediction and Engineering. Nat

Rev Drug Discov. 2004, 3 (1), 42-57. 2. Huang, L.F.; Tong, W.Q., Impact of solid state properties on developability assessment of drug candidates. Adv. Drug Delivery Rev. 2004, 56 (3), 321-334. 3.

Sun, C. C., Materials Science Tetrahedron- a useful Tool for Pharmaceutical Research and Development. J.

Pharm. Sci. 2009, 98 (5), 1671-1687. 4.

Yu, L., Amorphous Pharmaceutical Solids: Preparation, Characterization and Stabilization. Adv. Drug Delivery

Rev. 2001, 48 (1), 27-42. 5.

Law, D.; Schmitt, E. A.; Marsh, K. C.; Everitt, E. A.; Wang, W.; Fort, J. J.; Krill, S. L.; Qiu, Y., Ritonavir-PEG 8000

Amorphous Solid Dispersions: in Vitro and in Vivo Evaluations. J. Pharm. Sci. 2004, 93 (3), 563–570. 6.

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

Pharmaceuticals: I. A Thermodynamic Analysis. J. Pharm. Sci. 2010, 99 (3), 1254-1264. 7.

Alonzo, D. E.; Zhang, G. G. Z.; Zhou, D.; Gao, Y.; Taylor, L. S., Understanding the Behavior of Amorphous

Pharmaceutical Systems during Dissolution. Pharm. Res. 2010, 27 (4), 608-618. 8.

Babu, N. J.; Nangia, A., Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals. Cryst.

Growth Des. 2011, 11 (7), 2662-2679. 9.

Kanaujia, P.; Poovizhi, P.; Ng, W. K.; Tan, R. B. H., Amorphous formulations for dissolution and bioavailability

enhancement of poorly soluble APIs. Powder Technol. 2015, 285, 2-15. 10. Vasconcelos, T.; Sarmento, B.; Costa, P., Solid Dispersion as Strategy to Improve Oral Bioavailability of Poor Water Soluble Drugs. Drug Discovery Today 2007, 12 (23-24), 1068-1075. 11. Cai, T.; Zhu, L.; Yu, L., Crystallization of Organic Glasses: Effects of Polymer Additives on Bulk and Surface Crystal Growth in Amorphous Nifedipine. Pharm. Res. 2011, 28 (10), 2458-2466. 12. Mistry, P.; Suryanarayanan, R., Strength of Drug–Polymer Interactions: Implications for Crystallization in Dispersions. Cryst. Growth Des. 2016, 16 (9), 5141-5149. 13. Huang, C.; Powell, C. T.; Sun, Y.; Cai, T.; Yu, L., Effect of Low-Concentration Polymers on Crystal Growth in Molecular Glasses: A Controlling Role for Polymer Segmental Mobility Relative to Host Dynamics. J. Phys. Chem. B 2017, 121 (8), 1963-1971. 14. Kestur, U. S.; Taylor, L. S., Role of Polymer Chemistry in Influencing Crystal Growth Rates from Amorphous Felodipine. CrystEngComm 2010, 12 (8), 2390-2397. ACS Paragon Plus Environment

Page 26 of 31

Page 27 of 31

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

Molecular Pharmaceutics 15. Matsumoto, T.; Zografi, G., Physical Properties of Solid Molecular Dispersions of Indomethacin with Poly(vinylpyrrolidone) and Poly(vinylpyrrolidone-co-vinyl-acetate) in Relation to Indomethacin Crystallization. Pharm. Res. 1999, 16 (11), 1722-1728. 16. Szczurek, J.; Rams-Baron, M.; Knapik-Kowalczuk, J.; Antosik, A.; Szafraniec, J.; Jamroz, W.; Dulski, M.; Jachowicz, R.; Paluch, M., Molecular Dynamics, Recrystallization Behavior, and Water Solubility of the Amorphous Anticancer Agent Bicalutamide and Its Polyvinylpyrrolidone Mixtures. Mol. Pharmaceutics 2017, 14 (4), 1071-1081. 17. Shamblin, S. L.; Zografi, G., Enthalpy Relaxation in Binary Amorphous Mixtures Containing Sucrose. Pharm. Res. 1998, 15 (12), 1828-1834. 18. Khougaz, K.; Clas, S. D., Crystallization Inhibition in Solid Dispersions of MK‐0591 and Poly(vinylpyrrolidone) Polymers. J. Pharm. Sci. 2000, 89 (10), 1325-1334. 19. 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. Mol. Pharmaceutics 2015, 12 (1), 162-170. 20. 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. Mol. Pharmaceutics 2015, 12 (9), 3339-3350. 21. Powell, C. T.; Cai, T.; Hasebe, M.; Gunn, E. M.; Gao, P.; Zhang, G.; Gong, Y.; Yu, L., Low-Concentration Polymers Inhibit and Accelerate Crystal Growth in Organic Glasses in Correlation with Segmental Mobility. J. Phys. Chem. B 2013, 117 (35), 10334-10341. 22. Shi, Q.; Zhang, C.; Su, Y.; Zhang, J.; Zhou, D.; Cai, T., Acceleration of Crystal Growth of Amorphous Griseofulvin by Low-Concentration Poly(ethylene oxide): Aspects of Crystallization Kinetics and Molecular Mobility. Mol. Pharmaceutics 2017, 14(7), 2262-2272. 23. Sato, T.; Taylor, L. S., Acceleration of the Crystal Growth Rate of Low Molecular Weight Organic Compounds in Supercooled Liquids in the Presence of Polyhydroxybutylate. CrystEngComm 2017, 19, 80-87. 24. Kestur, U. S.; Taylor, L. S., Evaluation of the Crystal Growth Rate of Felodipine Polymorphs in the Presence and Absence of Additives As a Function of Temperature. Cryst. Growth Des. 2013, 13 (10), 4349-4354. 25. Zhang, S.; Britten, J. F.; Chow, A. H. L.; Lee, T. W. Y., Impact of Crystal Structure and Polymer Excipients on the Melt Crystallization Kinetics of Itraconazole Polymorphs. Cryst. Growth Des. 2017, 17(6), 3433-3442. 26. Sun, Y.; Tao, J.; Zhang, G. G.; Yu, L., Solubilities of Crystalline Drugs in Polymers: an Improved Analytical Method and Comparison of Solubilities of Indomethacin and Nifedipine in PVP, PVP/VA, and PVAc. J. Pharm. Sci. 2010, 99 (9), 4023-4031. 27. Marsac, P. J.; Shamblin, S. L.; Taylor, L. S., Theoretical and Practical Approaches for Prediction of Drug– ACS Paragon Plus Environment


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

Polymer Miscibility and Solubility. Pharm. Res. 2006, 23 (10), 2417-2426. 28. Tao, J.; Sun, Y.; Zhang, G. G.; Yu, L., Solubility of Small-Molecule Crystals in Polymers: D-mannitol in PVP, Indomethacin in PVP/VA, and Nifedipine in PVP/VA. Pharm. Res. 2009, 26 (4), 855-864. 29. Wu, T.; Yu, L., Origin of Enhanced Crystal Growth Kinetics near Tg Probed with Indomethacin Polymorphs. J. Phys. Chem. B 2006, 110 (32), 15694-15699. 30. Taylor, L. S.; Zografi. G, Spectroscopic Characterization of Interaction between PVP and Indomethacin in Amorphous Molecular Dispersion. Pharm. Res. 1997, 14 (12), 1691-1698. 31. Van Duong, T.; Van Humbeeck, J.; Van den Mooter, G., Crystallization Kinetics of Indomethacin/Polyethylene Glycol Dispersions Containing High Drug Loadings. Mol. Pharmaceutics 2015, 12 (7), 2493-2504. 32. Van Duong, T.; Reekmans, G.; Venkatesham, A.; Van Aerschot, A.; Adriaensens, P.; Van Humbeeck, J.; Van den Mooter, G., Spectroscopic Investigation of the Formation and Disruption of Hydrogen Bonds in Pharmaceutical Semicrystalline Dispersions. Mol. Pharmaceutics 2017, 14 (5), 1726-1741. 33. Chen, Z.; Liu, Z.; Qian, F., Crystallization of Bifonazole and Acetaminophen within the Matrix of Semicrystalline, PEO-PPO-PEO Triblock Copolymers. Mol. Pharmaceutics 2015, 12 (2), 590-599. 34. Carpentier, L.; Decressain, R.; S. Desprez, A.; Descamps, M., Dynamics of the Amorphous and Crystalline α-, γ-Phases of Indomethacin. J. Phys. Chem. B 2006, 110 (1), 457-464. 35. Wojnarowska, Z.; Adrjanowicz, K.; Wlodarczyk, P.; Kaminska, E.; Kaminski, K.; Grzybowska, K.; Wrzalik, R.; Paluch, M.; Ngai, K. L., Broadband Dielectric Relaxation Study at Ambient and Elevated Pressure of Molecular Dynamics of Pharmaceutical: Indomethacin. J. Phys. Chem. B 2009, 113 (37), 12536-12545. 36. Ishida, H.; Wu, T.; Yu, L., Sudden Rise of Crystal Growth Rate of Nifedipine near T(g) without and with Polyvinylpyrrolidone. J. Pharm. Sci. 2007, 96 (5), 1131-1138. 37. Trasi, N. S.; Taylor, L. S., Effect of Additives on Crystal Growth and Nucleation of Amorphous Flutamide. Cryst. Growth Des. 2012, 12 (6), 3221-3230. 38. Kestur, U. S.; Lee, H.; Santiago, D.; Rinaldi, C.; Won, Y.-Y.; Taylor, L. S., Effects of the Molecular Weight and Concentration of Polymer Additives, and Temperature on the Melt Crystallization Kinetics of a Small Drug Molecule. Cryst. Growth Des. 2010, 10 (8), 3585-3595. 39. Kaminska, E.; Madejczyk, O.; Tarnacka, M.; Jurkiewicz, K.; Kaminski, K.; Paluch, M., Studying of crystal growth and overall crystallization of naproxen from binary mixtures. Eur. J. Pharm. Biopharm. 2017, 113, 75-87. 40. Madejczyk, O.; Kaminska, E.; Tarnacka, M.; Dulski, M.; Jurkiewicz, K.; Kaminski, K.; Paluch, M., Studying the Crystallization of Various Polymorphic Forms of Nifedipine from Binary Mixtures with the Use of Different Experimental Techniques. Mol. Pharmaceutics 2017, 14 (6), 2116-2125. 41. Grzybowska, K.; Capaccioli, S.; Paluch, M., Recent Developments in the Experimental Investigations of Relaxations in Pharmaceuticals by Dielectric Techniques at Ambient and Elevated Pressure. Adv. Drug Delivery Rev. ACS Paragon Plus Environment

Page 28 of 31

Page 29 of 31

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

Molecular Pharmaceutics 2016, 100, 158-182. 42. Sun, Y.; Xi, H.; Ediger, M. D.; Richert, R.; Yu, L., Diffusion-Controlled and "Diffusionless" Crystal Growth near the Glass Transition Temperature: Relation between Liquid Dynamics and Growth Kinetics of Seven ROY Polymorphs. J. Chem. Phys. 2009, 131 (7), 074506. 43. Zhao, J.; Ediger, M. D., Segmental Dynamics of Dilute Poly(ethylene oxide) in Low and High Molecular Weight Glass-Formers. Macromolecules 2011, 44 (22), 9046-9053. 44. Ediger, M. D.; Harrowell, P.; Yu, L., Crystal Growth Kinetics Exhibit a Fragility-Dependent Decoupling from Viscosity. J. Chem. Phys. 2008, 128 (3), 034709. 45. Swallen, S. F.; Ediger, M. D., Self-Diffusion of the Amorphous Pharmaceutical Indomethacin near Tg. Soft Matter 2011, 7 (21), 10339-10344. 46. Mapes, M. K.; Swallen, S. F.; Ediger, M. D., Self-Diffusion of Supercooled o-terphenyl near the Glass Transition Temperature. J. Phys. Chem. B 2006, 110 (1), 507-511. 47. Ngai, K. L.; Magill, J. H.; Plazek, D. J., Flow, Diffusion and Crystallization of Supercooled Liquids: Revisited. J. Chem. Phys. 2000, 112 (4), 1887-1892. 48. Tarjus, G.; Kivelson, D., Breakdown of the Stokes–Einstein Relation in Supercooled Liquids. J. Chem. Phys. 1995, 103 (8), 3071-3073. 49. Grzybowska, K.; Paluch, M.; Grzybowski, A.; Wojnarowska, Z.; Hawelek, L.; Kolodziejczyk, K.; Ngai, K. L. Molecular Dynamics and Physical Stability of Amorphous Anti-Inflammatory Drug: Celecoxib. J. Phys. Chem. B 2010, 114 (40), 12792−12801. 50. Mehta, M.; Kothari, K.; Ragoonanan, V.; Suryanarayanan, R., Effect of Water on Molecular Mobility and Physical Stability of Amorphous Pharmaceuticals. Mol. Pharmaceutics 2016, 13 (4), 1339-1346. 51. Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S., Inhibition of Solution Crystal Growth of Ritonavir by Cellulose Polymers- Factors Influencing Polymer Effectiveness. CrystEngComm 2012, 14 (20), 6503-6514. 52. Kubota, N.; Yokota, M.; Mullin, J. W., The Combined Influence of Supersaturation and Impurity Concentration on Crystal Growth. J. Cryst. Growth 2000, 212 (3–4), 480-488. 53. Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S., Understanding Polymer Properties Important for Crystal Growth Inhibition- Impact of Chemically Diverse Polymers on Solution Crystal Growth of Ritonavir. Cryst. Growth Des. 2012, 12 (6), 3133-3143. 54. Patel, D. D.; Anderson, B. D., Adsorption of Polyvinylpyrrolidone and its Impact on Maintenance of Aqueous Supersaturation of Indomethacin via Crystal Growth Inhibition. J. Pharm. Sci. 2015, 104 (9), 2923-2933. 55. Schram, C. J.; Beaudoin, S. P.; Taylor, L. S., Polymer Inhibition of Crystal Growth by Surface Poisoning. Cryst. Growth Des. 2016, 16 (4), 2094-2103. 56. Alonzo, D. E.; Raina, S.; Zhou, D.; Gao, Y.; Zhang, G. G. Z.; Taylor, L. S., Characterizing the Impact of ACS Paragon Plus Environment


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

Hydroxypropylmethyl Cellulose on the Growth and Nucleation Kinetics of Felodipine from Supersaturated Solutions. Cryst. Growth Des. 2012, 12 (3), 1538-1547. 57. Terry, A.; Martin; Tracie, L.; Potapenko; Sergey; Palmore; Tayhas, G.; Yoreo, D.; James, J., Recovery of Surfaces from Impurity Poisoning during Crystal Growth. Nature 1999, 399 (6735), 442-445. 58. Schram, C. J.; Beaudoin, S. P.; Taylor, L. S., Impact of Polymer Conformation on the Crystal Growth Inhibition of a Poorly Water-Soluble Drug in Aqueous Solution. Langmuir 2015, 31 (1), 171-179. 59. Schram, C. J.; Taylor, L. S.; Beaudoin, S. P., Influence of Polymers on the Crystal Growth Rate of Felodipine – Correlating Adsorbed Polymer Surface Coverage to Solution Crystal Growth Inhibition. Langmuir 2015, 31 (41), 11279-11287. 60. Ilevbare, G. A.; Liu, H.; Edgar, K. J.; Taylor, L. S., Maintaining Supersaturation in Aqueous Drug Solutions: Impact of Different Polymers on Induction Times. Cryst. Growth Des. 2013, 13 (2), 740-751. 61. Raina, S. A.; Alonzo, D. E.; Zhang, G. G.; Gao, Y.; Taylor, L. S., Impact of Polymers on the Crystallization and Phase Transition Kinetics of Amorphous Nifedipine during Dissolution in Aqueous Media. Mol. Pharmaceutics 2014, 11 (10), 3565-3576. 62. Diao, Y.; Whaley, K. E.; Helgeson, M. E.; Woldeyes, M. A.; Doyle, P. S.; Myerson, A. S.; Hatton, T. A.; Trout, B. L., Gel-Induced Selective Crystallization of Polymorphs. J. Am. Chem. Soc. 2012, 134 (1), 673-684. 63. Zhu, Q.; Shtukenberg, A. G.; Carter, D. J.; Yu, T. Q.; Yang, J.; Chen, M.; Raiteri, P.; Oganov, A. R.; Pokroy, B.; Polishchuk, I.; Bygrave, P. J.; Day, G. M.; Rohl, A. L.; Tuckerman, M. E.; Kahr, B., Resorcinol Crystallization from the Melt: A New Ambient Phase and New "Riddles". J. Am. Chem. Soc. 2016, 138 (14), 4881-4889.


Page 30 of 31

Page 31 of 31

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


Table of Contents Graphic

Selective Acceleration of Crystal Growth of Indomethacin Polymorphs by Low-Concentration Poly(ethylene oxide) Qin Shi†, Jie Zhang†, Chen Zhang§, Jing Jiang§, Jun Tao†, Dongshan Zhou§, Ting Cai*,†, ‡ †State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China ‡Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China §Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China


Selective Acceleration of Crystal Growth of Indomethacin Polymorphs

Recommend Documents