Effect of Binary Additive Combinations on Solution Crystal Growth of

Article pubs.acs.org/crystal

Effect of Binary Additive Combinations on Solution Crystal Growth of the Poorly Water-Soluble Drug, Ritonavir Published as part of a Crystal Growth & Design virtual special issue of selected papers presented at the 10th International Workshop on the Crystal Growth of Organic Materials (CGOM10). Grace A. Ilevbare,1 Haoyu Liu,2 Kevin J. Edgar,2 and Lynne S. Taylor1,* 1 2

Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana Department of Sustainable Biomaterials, College of Natural Resources and Environment, Virginia Tech, Blacksburg, Virginia S Supporting Information *

ABSTRACT: Combinations of additives (polymers and surfactants) are often used in pharmaceutical products to improve the delivery of poorly water-soluble active pharmaceutical ingredients (API). Additive interactions have not been widely studied and may promote or inhibit crystallization (nucleation and crystal growth) in an unpredictable manner, which in turn has an impact on the extent and duration of supersaturation. In this study, the effect of a series of polymer/polymer and polymer/ surfactant combinations on crystal growth inhibition was investigated. Surprisingly, the majority of the polymer/polymer combinations investigated had a synergistic effect on crystal growth inhibition. The effectiveness of the polymer/polymer combinations was ascribed to the formation of interpolymer complexes through hydrophobic interactions that adsorb and interact favorably with the crystallizing solute and/or, interaction of individual polymers at different adsorption sites. The acceleration of crystal growth in the presence of polymer/surfactant combinations was attributed to weakened interactions between the polymer and the surface of the crystallizing solute brought about by the presence of surfactant molecules. Based on these observations, careful evaluation of the impact of combinations of additives on crystallization behavior is recommended in order to optimize the performance of supersaturating dosage forms.

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polymer/surfactant mixtures in solution.7−9,18−23 Examples of polymer and surfactant that have been studied in this context include interactions between poly(ethylene glycol) (PEG) and polysorbate 80,23,24 hydroxypropyl methyl cellulose (HPMC) and poloxamer,22 HPMC and polysorbate 80,25 and poly(vinylpyrrolidone) PVP and sodium lauryl sulfate (SLS).26 Polymer/polymer interactions of synthetic polycarboxylic acid polymers such as poly(methacrylic acid) (PMAA) or poly (acrylic acid) (PAA) with PEG and PVP have also been examined.4,27 For example, when HPMC was combined with poloxamer and polyoxyethylene hydrogenated castor oil to produce amorphous solid dispersions of felodipine, a remarkable increase in dissolution rate and solubility of felodipine was achieved.22 In addition, a study performed by Dannenfelser et al. (2004) highlighted the improvement in dissolution rate and bioavailability of a poorly water-soluble drug (LAB68) after being dispersed in a mixture of PEG and polysorbate 80.23 The presence of a hydrophilic additive (such as a surfactant or very hydrophilic polymer) in a formulation containing a polymeric carrier may help prevent precipitation

INTRODUCTION The associations between combinations of polymers and those of polymer/surfactant systems in aqueous solution have garnered considerable fundamental and technological interest. The species resulting from the interactions of these molecules possess unique properties that differ from those of the individual components. As a result, they have important applications in industrial and biological processes.1 For example, polymer and surfactant combinations have been used for rheology control2 and immobilization of enzymes in polyelectrolyte complexes,3 while synthetic water-soluble polymer combinations have been used in mineral-processing operations such as flocculation.4−6 In the drug delivery field, polymers and surfactants are often incorporated in formulations to modify the solubility of drugs with low aqueous solubility and to control the release rate. Thus, associations between polymers and surfactants are highly relevant, since pharmaceutical formulations often contain both component types.7−9 Formulations containing the drug as a high-energy amorphous solid can enhance drug delivery by generating supersaturated solutions.10,11 Polymers are typically incorporated to delay drug crystallization,12−15 and surfactants are frequently added to improve processing properties16 or dissolution profiles.17 A significant amount of research has been directed toward investigating the associations between polymer mixtures and © 2012 American Chemical Society

Received: August 13, 2012 Revised: October 22, 2012 Published: November 6, 2012 6050

dx.doi.org/10.1021/cg301169t | Cryst. Growth Des. 2012, 12, 6050−6060

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and/or protect a fine crystalline precipitate from agglomerating into larger aggregates.28 However, there has been no systematic study of the interplay between different additives in terms of the impact on crystallization, although such an interplay could be very influential on the performance of the dosage form. Additives such as polymers and surfactants are well-known to impact crystallization and may accelerate, inhibit, or totally suppress nucleation and crystal growth, depending on their effect on solution properties and crystallizing solute.29,30 This is important in the context of dosage forms where the goal is to maintain supersaturation for prolonged periods of time. It is thus important to probe the effect of additive combinations on the crystallization of poorly water-soluble drugs from supersaturated solutions, since the interaction between additives can result in changes in system properties which may result in a favorable or adverse effect on the inhibition of crystallization. The aim of this study was to investigate the effect of a number of binary-additive combinations (polymer/polymer and polymer/surfactant combinations) on the crystal growth of the poorly water-soluble model compound, ritonavir. This study was motivated by the fact that multiple additives may be present in a supersaturating dosage formulation. A variety of polymers, previously investigated individually as crystal growth inhibitors for ritonavir,31 were selected and used in various combinations in this study. The dominant interactive force between selected additive combinations and the crystallizing solute was also investigated by varying the ionic strength of the medium.

Table 1. Abbreviations for Polymers Used in This Study polymer

abbrev

poly(vinylpyrrolidone) (K 29/32) poly(vinylpyrrolidone vinyl acetate) (K 28) poly(allylamine) poly(N-isopropylacrylamide) poly(4-vinylpyridine N-oxide) cellulose acetate phthalate hydroxypropyl methyl cellulose (606 grade) hydroxypropyl methyl cellulose acetate succinate (AS-MF) cellulose propionate adipate cellulose acetate 320S adipate cellulose acetate propionate 504−0.2 adipate 0.85 cellulose acetate butyrate 553−0.4 adipate 0.81 cellulose acetate propionate 504−0.2 adipate 0.33 cellulose acetate butyrate 553−0.4 adipate 0.25

PVP PVPVA PAlAmn Pn-IPAAmd PVPdn-O CAPh HPMC HPMCAS CP Adp CA 320S Adp CAP Adp 0.85 CAB Adp 0.81 CAP Adp 0.33 CAB Adp 0.25

scheme for the novel cellulose ester polymers (Figure 2) is presented in ref 31 while a detailed description of the synthesis

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MATERIALS Ritonavir (Figure 1) was purchased from Attix Corporation, Toronto, Ontario, Canada. Acetonitrile and methanol were

Figure 2. Molecular structure of the novel synthesized cellulose derivatives and the substituent groups. These cellulose derivatives are not regioselectivity substituted, and particular positions of substitution are shown only for convenience of depiction. The abbreviations are presented in Table 1.

is discussed in ref 32. The general description and important properties of the newly synthesized cellulose derivatives is also presented in ref 31.

Figure 1. Molecular structure of ritonavir.

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METHODS Solubility Studies. The equilibrium solubility of ritonavir was determined in the absence and presence of selected additives (polymers and surfactants). Prior to adding an excess amount of ritonavir to 100 mM sodium phosphate buffer, pH 6.8, additives were predissolved in the buffer at a concentration of 5 μg/mL. The drug-additive solution was equilibrated at 37 °C for 48 h. Using ultracentrifugation, the supernatant was separated from the excess solid in solution. Ultracentrifugation was performed at 40,000 rpm (equivalent of 274356g) in an Optima L-100 XP ultracentrifuge equipped with a SwingingBucket Rotor SW 41 Ti (Beckman Coulter, Inc., Brea, CA). The supernatant was diluted using a combination of mobile phase solvents. Solution concentration was determined using an Agilent 1100 high performance liquid chromatography

purchased from Macron Chemicals (Phillipsburg, NJ). The commercially available polymers were acquired from various sources: poly(vinyl pyrrolidone) K29/32, cellulose acetate phthalate (Sigma-Aldrich Co., St. Louis, MO), poly(vinyl pyrrolidone/vinyl acetate) copolymer K28 (BASF, Germany), hydroxypropyl methyl cellulose 606 grade and hydroxypropyl methyl cellulose acetate succinate AS-MF grade (Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan)), poly(allylamine), poly(Nisopropylacrylamide), and poly(4-vinylpyridine N-oxide) (Polysciences, Inc., Warrington, PA). Tocopherol polyethylene glycol 1000 succinate was purchased from Eastman Chemical Company (Kingsport, TN), while Tween 80 was purchased from Sigma-Aldrich (St. Louis, MO). The abbreviations used in this report for the commercially available and newly synthesized polymers are presented in Table 1. The general synthesis 6051



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patterns were obtained within a scan range from 5 to 35° 2θ, with a scanning speed of 4°/min. Characterization of Polymers. The relative hydrophobicity of the polymers was characterized using solubility parameter (SP) values. SP values were estimated using the method proposed by Fedors.33 The method is based on group additive constants, and the contribution of a large number of functional groups was evaluated; therefore, it requires only knowledge of the structural formula of the polymer. The solubility parameter can be evaluated using the following:33

(HPLC) system (Agilent Technologies, Santa Clara, CA). Ritonavir was detected by ultraviolet (UV) absorbance at a wavelength of 240 nm. The chromatographic separation was performed with a Zobrax SB-C18 analytical column (150 mm × 2.1 mm i.d., 5 μm, 100 Å) (Agilent Technologies, Santa Clara, CA). A mixture of sodium phosphate buffer (10 mM, pH 6.8) (40%) and acetonitrile (60%) was used as mobile phase, and mobile phase flow was maintained at 0.2 mL/min. The injection volume was 20 μL. The total analytical run time was 20 min. Ritonavir standards (0.5−20 μg/mL) were prepared in methanol. The standards and samples were analyzed in triplicate. The standard curve exhibited good linearity (r2 > 0.9995) over the concentration range. The regression intercept for the calibration curve was very small and was not statistically significant compared to zero. Characterization of Seed Crystals. Ritonavir seed crystals were characterized using scanning electron microscopy (SEM), powder X-ray diffraction analysis (PXRD), and differential scanning calorimetry (DSC). SEM was used to determine the size and shape of ritonavir crystals, while PXRD and DSC were used to evaluate the polymorph of the seed crystals. Ritonavir was used as received from the manufacturer, and prior to use, the seeds were sieved to a size below 250 μm. Seed crystals used for SEM analysis were prepared by dispersing the seeds in water and equilibrating the water−seed crystal suspension for approximately 24 h. A few drops of the suspension was placed on a glass slide and dried overnight in a vacuum oven at room temperature for approximately 24 h. Before SEM imaging, the glass slides were mounted using double-sticky copper tape and sputter-coated with platinum for 60 s. SEM imaging was performed using an FEI NOVA nanoSEM field emission SEM using an Everhart-Thornley (ET) detector and a through-thelens detector (TLD). The following imaging parameters were used: 5 kV accelerating voltage, ∼4−5 mm working distance, beam spot size of 3, 30 μm aperture, and 100−10,000× magnifications. The SEM images were analyzed using ImageJ, processing and analysis in Java (National Institutes of Health (NIH)). Several representative samples of seed crystals were obtained before and after crystal growth in the absence and presence of predissolved additive. For each sample, a total of 50 seeds were analyzed to ensure a representative sample, and the average aspect ratio of the crystals was estimated from the average length and width of the crystals. DSC analysis was performed using a TA Instruments Q2000 instrument (TA Instruments, New Castle, DE) attached to a refrigerated cooling accessory (RCS) (TA Instruments, New Castle, DE). Both the DSC and RCS were purged with nitrogen gas. The thermogram of ritonavir was obtained by heating the sample at a rate of 5 °C/min and 20 °C/min for melting point and glass transition temperature determinations, respectively. Melting point was determined from a first heat scan, while the glass transition temperature was determined from a second heat scan. The temperature range used was 25− 150 °C. Thermal transitions were viewed and analyzed using the analysis software Universal Analysis 2000 for Windows 2000/XP provided with the instrument. PXRD patterns were obtained using a Shimadzu XRD 6000 diffractometer (Shimadzu Scientific Instruments. Columbia, Maryland). Calibration was performed using a silicon standard that has a characteristic peak at 28.44° 2θ. Experiments were performed using an accelerating potential of 40 kV and a current of 30 mA. The divergence and scattering slits were set at 1.0°, and the receiving slit was set at 0.3 mm. Diffraction

δ=

∑i Δei ∑i Δvi

=

ΔEv V

(1)

where the Δei and Δvi are the additive atomic and group contributions for the energy of vaporization and molar volume, respectively. Crystal Growth Rate. The crystal growth rate of ritonavir was characterized by measuring the rate of desupersaturation in the presence of seed crystals. Crystal growth rate experiments were performed in the absence and presence of predissolved additives at initial ritonavir concentrations of 5, 10, and 20 μg/ mL; all experiments were performed in triplicate. Additive concentrations of 5 μg/mL were used; in experiments where a combination of additives was used, the concentration of each additive in solution was 5 μg/mL (unless otherwise specified). Crystal growth experiments were performed in a jacketed beaker connected to a digitally controlled temperature water bath. Solubilized ritonavir was prepared by dissolving 200 mg of ritonavir in 50 mL of methanol to make a final stock solution of 4 mg/mL. Supersaturated solutions were generated by adding a small volume (0.25 mL) of predissolved ritonavir in methanol to sodium phosphate buffer, pH 6.8 (50 mL); the volume of methanol in buffer solution (1:200, methanol to buffer solution) did not have an impact on the equilibrium solubility of ritonavir. Prior to addition of solubilized ritonavir, seed crystals (0.010 g) were added to the buffer and allowed to equilibrate at 37 °C. Data collection began immediately after generation of supersaturation; the experiment duration was 30 min. The test solution was stirred at a constant speed of 400 rpm using a Cole Parmer (model 50000-20) overhead mixer attached to an axial-flow impeller blade, with a digital mixer controller (Cole Parmer Instrument Co., Niles, IL). The rate of desupersaturation of ritonavir was measured using a UV spectrometer coupled to a fiber optic probe, path-length 5 mm (SI Photonics, Tuscon, Arizona), at a constant temperature of 37 °C. Data was acquired at 5 s time intervals within a wavelength range of 200−450 nm. The slope of the concentration versus time curve over the first 2 min of the experiment was taken as the initial crystal growth rate. In order to mitigate particle scattering effects, second derivatives (SIMCA P+ V. 12 software (Umetrics Inc., Umea Sweden)) of the spectra as well as the calibration spectra were taken for the sample data. Calibration solutions (1−30 μg/mL) were prepared in methanol. The standard curve was linear over the above-mentioned concentration range (r2 > 0.999). Polymer/ polymer interactions were further investigated by performing growth experiments in sodium phosphate buffer at two different ionic strengths, 50 and 100 mM.

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RESULTS Solubility Studies. Supersaturation ratio is expressed as follows:

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S=

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c c0

Form II ritonavir.36 PXRD and DSC analysis further confirmed the crystalline form of ritonavir as Form II. The predicted powder pattern of ritonavir polymorphic Form II (CSD code: YIGPIO01), obtained from the Cambridge Structural Database (CSD) using the powder pattern prediction tool, is consistent with the measured PXRD pattern. However, the predicted crystal morphology (BFDH morphology prediction tool in Mercury) is more rodlike than the needles observed experimentally. The melting point and glass transition temperature (measured for the cooled melt) of the seed crystals were 121.0 and 50 °C, respectively. These values are consistent with those reported by Law et al. (2001)35 for the Form II polymorph of ritonavir and glassy ritonavir, respectively. The polymorphic form of the seeds crystals after the crystal growth experiment was also confirmed to be Form II by PXRD. The average length, width, and aspect ratio of ritonavir seed crystals before and after the crystal growth experiment in the presence of the CAP 0.85, Pn-IPAAmd, and CAP 0.85/Pn-IPAAmd polymer combination at initial S values of 7.6 and 15.4 are summarized in Table 4. In general, the seeds extracted after

(2)

where c is the concentration of the supersaturated solution and c0 is the equilibrium solubility at a given temperature. The equilibrium solubility of ritonavir (Form II) at pH 6.8 and 37 °C (100 mM phosphate buffer) was determined to be 1.3 ± 0.10 μg/mL. Ritonavir, a very weak base, is un-ionized at pH 6.8 (pKa’s are 1.8 and 2.634). The equilibrium solution concentration of ritonavir in the presence of selected polymers, polymer combinations, and surfactant at a concentration of 5 μg/mL is summarized in Table 2. The equilibrium solubility of ritonavir did not change significantly in the presence of additives at a concentration of 5 μg/mL. Table 2. Equilibrium Solubility of Ritonavir (at pH 6.8 and 37 °C) in the Presence of Polymer at a Concentration of 5 μg/mL solubilityb (μg/mL)

additive CAP Adp 0.33 CAP Adp 0.85 Pn-IPAAmd CAP Adp 0.85/CAP Adp 0.33a CAP Adp 0.85/Pn-IPAAmda Tween 80

1.5 1.3 1.3 1.5 1.8 1.3

± ± ± ± ± ±

0.10 0.02 0.01 0.09 0.20 0.02

Table 4. Ritonavir Seed Crystal Size before and after Crystal Growth in the Absence and Presence of CAP Adp 0.85, PnIPAAmd, and CAP 0.85/Pn-IPAAmd (1:1 ratio, 5 μg/mL of each polymer) at an Initial S Value of 7.6 (10 μg/mL) and 15.4 (20 μg/mL)

A 1:1 (5 μg/mL of each polymer) ratio of polymer combination was used. bSolubility of ritonavir at pH 6.8, 37 °C in the absence of polymer is 1.3 ± 0.10 μg/mL.

a

length (μm) Before Crystal Growth RTVa 44.4 ± 15.2 After Crystal Growth (S = 7.6) RTVa 50.4 ± 18.6 RTV−CAP Adp 54.0 ± 18.8 0.85b 41.1 ± 16.5 RTV−Pn-IPAAmda RTV−CAP Adp 38.5 ± 11.6 0.85/Pn-IPAAmd After Crystal Growth (S = 15.4) RTV 50.9 ± 14.4 RTV−CAP Adp 0.85 40.9 ± 12.0 RTV−Pn-IPAAmd 41.6 ± 15.1 RTV−CAP Adp 37.2 ± 10.0 0.85/Pn-IPAAmd

Characterization of Polymers. The hydrophobicity ranking of the polymers based on SP values is summarized in Table 3. The calculated solubility parameters of the polymers Table 3. Solubility Parameter (SP) Values and Their Ranking for Polymers Used in This Study abbr

SP (MPa1/2)

SP ranking

PVP PVPVA PAlAmn Pn-IPAAmd PVPdn-O CAPh HPMC HPMCAS CP Adp CA 320S Adp CAP Adp 0.85 CAB Adp 0.81 CAP Adp 0.33 CAB Adp 0.25

28.39 25.77 20.70 22.64 32.24 22.48 22.68 22.44 23.28 22.95 21.27 20.86 20.56 20.05

2 3 12 7 1 8 6 9 4 5 10 11 13 14

width (μm)

aspect ratio

crystal morphologyc

5.8 ± 1.9

7.7

needle-like

5.7 ± 1.4 10.5 ± 4.1

8.8 5.2

needle-like rodlike

9.3 ± 2.5 8.0 ± 1.4

4.4 4.8

rodlike rodlike

4.2 5.4 5.6 5.7

+ 1.2 ± 1.2 ± 1.4 ± 1.2

12.1 7.6 7.4 6.5

needle-like needle-like needle-like needle-like

a

Values from ref 31. bValue from ref 38. cSee Figures S1−S3 in the Supporting Information for SEM micrographs.

crystal growth at S of 15.4 were more elongated compared to the seeds grown at an S of 7.6 in a similar polymer solution. For example, after crystal growth in the absence of polymer, at S values of 7.6 and 15.4, the aspect ratio (length/width) of the seed crystals was 7.7 and 12.1, respectively. The BFDH morphology predictor of Mercury (Cambridge Crystallographic Data Center, version 3.0.1) suggests that the fastest growth direction is along the a-axis (lengthwise direction) with four fast growing faces ((−1, 0, −1), (−1, −1, 0), (−1, 0, 1), (−1, 1, 0)) perpendicular to this direction.31 The presence of CAP Adp 0.85, Pn-IPAAmd, and their combination in solution inhibited the growth in the fastest growth (lengthwise) direction at both supersaturations and resulted in a decrease in the aspect ratio. It has been proposed that the strong crystal growth inhibitory ability of Pn-IPAAmd can be attributed to a combination of the moderate hydrophobicity of the polymer and fortuitous intermolecular hydrogen bonding to the fast growing faces at

ranged from 20.05 to 32.24 MPa1/2. The higher the solubility parameter of a polymer, the more hydrophilic it is. The most hydrophilic polymer, PVPdn-O, is ranked #1, and #14 represents the most hydrophobic polymer, CAB Adp 0.25. Characterization of Seed Crystals. SEM analysis was used to quantitatively characterize the seed crystals before and after crystal growth. Ritonavir is known to have five polymorphs; Form II is the most stable and least soluble polymorphic form of ritonavir.35 The Form II polymorph was the intended starting material for this study. The seed crystals were needle-like, which is the characteristic crystal habit of 6053



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Figure 3. Crystal growth rate effectiveness ratio of ritonavir in the presence of individual polymers and their combinations (1:1 ratio) at an initial ritonavir concentration of 10 μg/mL. The concentration of each polymer in solution was 5 μg/mL. Crystal growth rate experiments were performed in triplicate. Each column is an average of the effectiveness ratio, and error bars indicate one standard deviation. The y-axis is a ratio of the growth rate of ritonavir in the absence of polymer to the growth rate of ritonair in the presence of polymer. Polymers with a ratio >1 are considered effective crystal growth inhibitors. The blue and red columns represent the individual polymers, while the white columns with blue diagonal lines represent the polymer/polymer combinations.

the solid−liquid interface.31 The above-mentioned fast growth planes expose functional groups containing electronegative atoms such as carbonyl oxygen and nitrogen atoms from the thiazole functional group of ritonavir which can potentially interact with the amide group of Pn-IPAAmd. See Figures S1− S3 (Supporting Information) for SEM micrographs of seed crystals grown at initial S values of 7.7 and 15.4 in the absence and presence of CAP Adp 0.85, Pn-IPAAmd, and CAP Adp 0.85/Pn-IPAAmd. Crystal Growth Rate. When seeds are added to a supersaturated solution, the excess solute can be consumed by two mechanisms: (1) the seed crystals can grow to a larger size; (2) new additional crystals can be generated by primary and/or secondary nucleation, resulting in a distribution of particles of a smaller size than that of the added seed crystals.37 It was therefore important to determine the predominant mechanism of desupersaturation during this study. A strong indicator of primary or secondary nucleation events during a crystal growth experiment is that the particle size distribution (PSD) for product crystals exhibits bimodality, since smaller size crystals are formed.37 For the system studied herein, it appears that desupersaturation is mainly due to the bulk crystal growth of the seed crystals present in solution. Evidence for this is as follows: first, the PSD of the seed crystals extracted after growth experiments exhibited monomodality (Supporting Information Figure S4). Second, given the observed extent of desupersaturation of ritonavir at the end of the experiment (1.5 μg/mL in the absence of polymer) and the seed loading used (0.010 g) and assuming that no new crystals were formed, the theoretical increase in volume of seed crystals could be calculated. The theoretical value (3.17 × 10−17 m3) was found to be similar to the experimentally estimated increase in volume (7.19 × 10−17 m3), calculated from the average dimensions of the seed crystals before and after crystal growth in the absence of polymer at an initial S value of 7.6 (Table 4). This result suggests that significant secondary nucleation did

not occur during our experiments, since the increase in volume and mass of the seed crystals in solution accounts for the change in solute concentration (balanced mass transfer).37 Lastly, we evaluated the induction times for primary nucleation and the impact of some of the polymer combinations on the induction times. At an initial concentration of 20 μg/mL, the nucleation−induction of ritonavir alone is ∼2 h. An initial concentration of 20 μg/mL was used because, at 10 μg/mL (concentration used to screen additive combinations in this study), the nucleation rate of ritonavir is very slow; the nucleation−induction time was greater than 8 h (Supporting Information Figure S5). These data suggest that primary nucleation is unlikely to be a factor in the growth rate experiments; however, it is also necessary to check that the polymer combinations do not promote nucleation. No shortening of induction times was observed when the polymer combinations were used, with the polymers actually inhibiting nucleation. For example, the CAP Adp 0.85/HPMC polymer combination inhibited nucleation, increasing the induction time to ∼3 h. Incidentally, the polymer combination was not more effective at extending induction times than the individual polymers, unlike their impact on crystal growth rate, which is described below. A summary of the growth rate ratios of ritonavir in the absence of polymer (Rg0) to the growth rate of ritonavir in the presence of the polymers/polymer combination (5 μg/mL of each polymer, 1:1 ratio) investigated (Rgp) at an initial concentration of 10 μg/mL (S of 7.6) is shown in Figure 3. The initial bulk crystal growth rate (rate of desupersaturation during the first 2 min) of ritonavir in the 100 mM sodium phosphate buffer at an initial concentration of 10 μg/mL was 1.56 μg mL−1 min−1. At the end of the experiment (30 min), desupersaturation was complete. The red and blue columns represent the individual polymers, while the clear columns with diagonal lines represent the polymer/polymer pairs. Individual 6054



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polymers and polymer/polymer combinations with an effectiveness ratio greater than 1 (Rg0/Rgp > 1) are considered to have some inhibitory ability. Polymers with different structures were employed, of which 5 were synthetic polymers, 3 were commercially available cellulose-based polymers, and 6 were in-house synthesized cellulose derivative polymers with varying physical and chemical properties. Ten out of the 13 combinations that were investigated had a synergistic effect on growth inhibition; the combination of two polymers was more effective in inhibiting crystal growth compared to either of the individual polymers. Five out of the 10 effective polymer pairs were combinations of the adipate cellulose ester, CAP Adp 0.85, previously observed to be the most effective cellulose inhibitor studied to date for this system, with various synthetic polymers (e.g., PVP and PVPVA). The CAP Adp 0.85/PnIPAAmd polymer combination, which represents the pairing of the two most effective polymers, led to the greatest retardation of growth, where the crystal growth rate was decreased by a factor of 12. In contrast, each individual polymer component of this combination decreased the growth rate by a factor of ∼3. Interestingly, combining CAP Adp 0.85 with synthetic polymers that were ineffective alone resulted in enhanced growth rate inhibition. For example, although PVP had no impact on ritonavir growth rate alone, when added to CAP Adp 0.85, the ratio of the growth rates increased from approximately 3 to about 4.5. Somewhat surprisingly, combining chemically similar cellulose derivatives also lead to a synergistic effect on crystal growth in some cases with the most effective pairs (CA 320S Adp with CP Adp and CAP Adp 0.85 with CAP Adp 0.33) leading to an increase in the growth rate ratio to about 4.5. The polymer combinations containing CAB Adp 0.25 (CAP Adp 0.33/CAB Adp 0.25 and CAB Adp 0.85/CAB Adp 0.25) were the least effective of all the polymer combinations investigated. In addition, pairing CAP Adp 0.85 with either HPMCAS or CAPh did not inhibit crystal growth any further compared to CAP Adp 0.85 alone. So far, we have evaluated the effectiveness of individual polymers at a concentration of 5 μg/mL and compared their effectiveness to polymer combinations containing a 1:1 ratio of each individual polymer (5 μg/mL of each polymer). For the polymer combinations, the total concentration of polymer in solution was 10 μg/mL (5 μg/mL of each polymer). It was of interest to evaluate whether higher levels of inhibition could be achieved by the individual polymers by increasing the concentration of each individual polymer from 5 μg/mL to 10 μg/mL. Figure 4a shows a comparison between the crystal growth rate effectiveness ratio of CA 320S Adp and CP Adp at two polymer concentrations, 5 μg/mL and 10 μg/mL. At both polymer concentrations, the effectiveness of either polymer (CA 320S Adp or CP Adp) in inhibiting the crystal growth of ritonavir was relatively comparable. A column chart comparing the effectiveness of the CA 320S Adp and CP Adp (each at a polymer concentration of 10 μg/mL), and the CA 320S Adp/ CP Adp combinations (total polymer concentration in solution: 10 μg/mL) is shown in Figure 4b. Although the polymer concentration of the individually tested polymer was similar to the total concentration of polymer present in solution for the polymer combination, higher gains in effectiveness were achieved when the CA 320S Adp/CP Adp combination was used compared to when the polymers were used individually (Figure 4b).

Figure 4. (a) Comparison of the crystal growth rate effectiveness ratio of CA 320S Adp and CP Adp at two polymer concentrations, 5 and 10 μg/mL. (b) Comparison of the crystal growth rate effectiveness ratio CA 320S Adp and CP Adp at polymer concentrations of 10 μg/mL and CA 320S Adp/CP Adp polymer combination (1:1 ratio of each polymer, total polymer concentration in solution was 10 μg/mL). The polymer combination was more effective in inhibiting crystal growth of ritonavir compared to the individual polymers even at similar total polymer concentration.

The crystal growth rate effectiveness ratio of ritonavir in the presence of CA 320S Adp/CP Adp, one of the most effective cellulose polymer combinations, as a function of CA 320S Adp concentration is shown in Figure 5. The concentration of CP Adp was held constant at 5 μg/mL, while the concentration of CA 320S Adp ranged from 0 to 7.5 μg/mL. There was a notable increase in polymer/polymer combination effectiveness (factor of ∼2.5) when a small amount (0.5 μg/mL) of CA 320S Adp was added to a 5 μg/mL CP Adp solution. The effectiveness of the polymer combination in inhibiting crystal growth did not increase significantly when the concentration of CA 320S Adp was further increased. Figure 6 shows a comparison between the crystal growth effectiveness ratio of selected polymer combinations at two different ionic strengths [50 mM (white columns) and 100 mM (red columns)] at an initial ritonavir concentration of 10 μg/ mL. The crystalline solubilities of ritonavir in 50 mM and 100 mM sodium phosphate buffer are 2.3 ± 0.04 μg/mL and 1.3 ± 0.10 μg/mL, respectively. Therefore, on the basis of eq 2, the supersaturation ratio of ritonavir in 50 and 100 mM sodium phosphate buffer is 4.3 and 7.7, respectively. On the basis of previous observations that polymers are less effective growth 6055



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combinations were more effective in inhibiting crystal growth relative to the growth in the absence of the polymer at the higher ionic strength, as shown in Figure 6. Furthermore, the largest relative difference in the growth rate ratio at the two different ionic strengths was observed for the more effective polymer pairs. The crystal growth rates of ritonavir as a function of supersaturation at constant ionic strength (100 mM sodium phosphate buffer) in the absence and presence of 4 out of the 13 investigated polymer combinations are shown in Figure 7.

Figure 5. Crystal growth rate effectiveness ratio for ritonavir as a function of CA 320S Adp concentration at an initial ritonavir concentration of 10 μg/mL. The concentration of CP Adp was held constant at 5 μg/mL, while the concentration of CA 320S Adp was varied. The experiments were performed in triplicate, and error bars represent one standard deviation.

Figure 7. Crystal growth rate of ritonavir at supersaturation ratios of 3.8, 7.6, and 15.3 in the absence and presence of polymer/polymer combinations (1:1 ratio, 5 μg/mL of each polymer): CAP Adp 0.85/ Pn-IPAAmd, CAP Adp 0.85/CAP Adp 0.33, CAP Adp 0.85/CA 320S Adp, and CAP Adp 0.85/PVP. The experiments were performed in triplicate, and error bars represent one standard deviation. Statistically, at S of 7.6, the polymer combinations between CAP Adp 0.85 and CAP Adp 0.33, CA 320S Adp, or PVP were equally effective.

The effectiveness of the polymer/polymer combinations varied depending on the extent of the supersaturation. At all supersaturations, crystal growth was reduced in the presence of the polymeric inhibitors, where the most significant decrease in growth rate was observed at the lowest S of 3.8. The CAP Adp 0.85/Pn-IPAAmd polymer combination completely inhibited crystal growth at this supersaturation. At the highest S of 15.4, the CAP Adp 0.85/Pn-IPAAmd combination resulted in a significant decrease in growth rate (a factor of 3.3 decrease in growth rate) compared to when CAP Adp 0.85 and PnIPAAmd are used individually, where crystal growth was inhibited to a much smaller extent (a factor of 1.4 and 1.6 reduction in growth rate, respectively) (Table 5). The crystal growth effectiveness ratio of the two surfactants investigated (TPGS and Tween 80) and the polymer/surfactant combinations of Tween 80 and the cellulose ester polymers, CAP Adp 0.33 and CAP Adp 0.85, are shown in Figure 8. In all experiments, the concentration of surfactants in solution is below the critical micelle concentration (CMC) of Tween 80 (0.018 mM ≈ 24 μg/mL in water)40 and TPGS (0.02 wt % ≈ 212 μg/mL at 37 °C),41 and the equilibrium solubility of ritonavir does not change in 5 μg/mL solutions of either surfactant. In the presence of the surfactants, the crystal growth rate of ritonavir increased by a factor of approximately 2, leading to Rg0/Rgp < 1. Although the polymers alone were able

Figure 6. Crystal growth rate effectiveness ratio of ritonavir at two ionic (sodium phosphate buffer) strength conditions (50 and 100 mM), at an initial ritonavir concentration of 10 μg/mL. The concentration of each polymer in solution was 5 μg/mL (1:1 ratio). At an initial concentration of 10 μg/mL, the supersaturation ratio of ritonavir in 50 and 100 mM sodium phosphate buffer is 4.3 and 7.7, respectively. Crystal growth rate experiments were performed in triplicate. Each column is an average of the effectiveness ratio, and error bars indicate one standard deviation. The y-axis is a ratio of the growth rate of ritonavir in the absence of polymer to the growth rate of ritonavir in the presence of polymer. Polymers with a ratio >1 are considered effective crystal growth inhibitors.

inhibitors at higher supersaturations,38,39 the crystal growth rate effectiveness ratio of the polymers in 50 mM is expected to be higher; however, this was not observed experimentally. Although the crystal growth rates were faster overall in 100 mM buffer due to the higher supersaturation, the polymer 6056



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also interact to form solution complexes, they may adsorb as a complex directly from solution or they may adsorb individually. In this case, there may be competition between the additives and the complex for adsorption sites.43,45 We can speculate on the origin of the growth modification observed for the systems investigated in this study, based on these scenarios. For the most effective polymer/polymer combination, CAP Adp 0.85/Pn-IPAAmd (Figure 3, the individual polymers were also the most effective individual inhibitors of ritonavir crystal growth31), given the dissimilarity of the chemical structures, it is quite likely that they adsorb, at least to some extent, to different sites at the solid−liquid interface, leading to the observed strongly synergistic effect. The strong inhibitory ability of the CAP Adp 0.85/Pn-IPAAmd combination may be partly attributed to intermolecular hydrogen bonding of PnIPAAmd to the fast growing faces at the solid−liquid interface.31,46 However, additional factors need to be considered for some of the cellulose derivative polymer pairs, which, rather unexpectedly given their similar chemistry, also produced synergistic effects on growth rate inhibition. For these systems, hydrophobic interactions may be important for determining whether synergistic interactions occur. Hydrophobic interactions, driven by the entropic gain accompanying this association,47 play an important role in the stabilization of interpolymer complexes which can form in aqueous solution.27,47,48 It can be noted that the relative hydrophobicity of each cellulose polymer tends to influence the level of effectiveness of the polymer combination. In general, pairing of two moderately hydrophobic polymers (e.g., CA 320S Adp/ CP Adp) was more effective than combination with the more hydrophobic polymers (e.g., polymer combinations with the most hydrophobic polymer CAB Adp 0.25). Thus, the pairing of the most effective cellulose ester, CAP Adp 0.85, with another moderately hydrophobic polymer (based on the solubility parameter hydrophobicity rankings shown in Table 3) resulted in additional reductions in crystal growth rate relative to each individual polymer, with two exceptions: CAP Adp 0.85/HPMCAS and CAP Adp 0.85/CAPh. The lack of synergy between CAP Adp 0.85 and either HPMCAS or CAPh suggests that these polymers may compete for the same adsorption sites, and being approximately equally effective on an individual basis, this results in no noticeable change in the extent of growth rate modification for the combination. In contrast, the combination of the chemically similar polymers, CAP Adp 0.85 and CAP Adp 0.33, which differ only in the degree of substitution (DS) of the adipate functionalities, is more effective than either individual polymer, suggesting the possibility of complex formation that enhances effectiveness. A number of interactive forces are responsible for the formation of complexes between two molecules, including electrostatic, hydrogen-bonding, hydrophobic interactions, or a combination of these forces.4 In this study, it is considered unlikely that electrostatic and hydrogen bonding are the dominant interactive forces responsible for the formation of complexes between polymers for the following reasons: Interspecies hydrogen bonding is not promoted in a highly hydrogen bonding solvent such as water. Water molecules strongly compete with directional polar interactions such as hydrogen bonds, resulting in low intermolecular hydrogen bonding between polymer molecules.49 Furthermore, the pKa of the adipate substituent is approximately 4.43,50 so the degree of ionization of the CO2H-containing substituent (adipate) (Figure 2) will be nearly complete (∼100%) at pH 6.8;51 thus,

Table 5. Crystal Growth Rate of Ritonavir at an Initial Concentration of 20 μg/mL in the Presence of Individual Polymers and Their Combination (1:1 ratio, 5 μg/mL of each polymer)a,b CAP Adp 0.85/PnIPAAmd CAP Adp 0.85/PVP

CAP Adp 0.85

Pn-IPAAmd

polymer comb.

2.5 ± 0.46 (1.4)

2.2 ± 0.12 (1.6)

1.1 ± 0.29 (3.3)

CAP Adp 0.85

PVP

polymer comb.

2.5 ± 0.46 (1.4)

3.6 ± 0.30 (1.0)

2.0 ± 0.24 (1.8)

a

The crystal growth effectiveness ratios of the polymers and polymer/ polymer combinations are in parentheses. bGrowth rate units: μg mL−1 min−1. Growth rate of ritonavir in the absence of polymer: 3.6 ± 0.17.

Figure 8. Crystal growth rate effectiveness ratio of ritonavir in the presence of surfactant only (white columns), polymer only (red columns), and polymer/surfactant combination (blue columns) at an initial ritonavir concentration of 10 μg/mL (S = 7.6). The concentration of each additive in solution was 5 μg/mL (1:1 ratio).

to reduce the growth rate by a factor of ∼2−3 (Figure 8), in the presence of the surfactants and cellulose polymer/surfactant combinations, the growth rate is actually faster than the growth rate of ritonavir in the absence of additives. In other words, the presence of Tween 80 significantly decreased the effectiveness of the polymers as growth rate inhibitors.

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DISCUSSION A consideration of the impact of multiple additives on solution crystal growth rates is important in complex systems such as pharmaceutical products, which frequently contain many different components. In the absence of additive effects on either supersaturation or solution viscosity, adsorption of additive molecules on the surface of crystals is a required step for modification of growth to occur.42 For binary additives, the following scenarios are possible, depending on the nature of the additives and the interface: (1) Both additives adsorb independently at the interface and may either interact with different surface adsorption sites or compete for adsorption sites.43,44 (2) If both additives adsorb at the surface and they 6057



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of supersaturated solutions and, thereby, bioavailability enhancement. It is also interesting that the ineffective synthetic polymer, PVP, has a synergistic effect when combined with CAP Adp 0.85, whereby crystal growth decreased by a factor of ∼2 at high supersaturation. This result is of practical importance, since more hydrophilic polymers, such as PVP, can be potentially combined with moderately hydrophobic polymers (CAP Adp 0.85) in amorphous matrices to improve drug release rates. Therefore, by judicious selection of polymer combinations, it may be possible to substantially delay crystal growth at the supersaturation generated by dissolution of the amorphous solid while concurrently improving formulation properties. In general, the additives discussed so far have either inhibited or had no effect on crystal growth. However, it is known that some additives can, in fact, accelerate crystal growth.53−55 Acceleration of crystal growth occurs when the thermodynamic effect of the adsorbed additive on the interfacial tension (adsorption leads to a decrease in interfacial tension which is favorable to growth29) outweighs any kinetic effects of the adsorbed additive, such as blocking kink growth sites. It has been observed that surfactants can either inhibit or promote crystal growth.53−57 In the case of the two surfactants studied, tocopheryl polyethylene glycol succinate (TPGS) and Tween 80 (Figure 8), ritonavir crystal growth is accelerated by a factor of ∼2. Surfactants are thought to promote crystal growth by two mechanisms: by solubilization, thereby concentrating solute molecules in micelles,53 or by decreasing interfacial tension and/or formation of surface clusters.58 Since the concentration of surfactant used in our studies is well below the critical micelle concentration (CMC), it appears that they promote crystal growth via adsorption and impacting the crystal−solution interface. The presence of surfactant in solution often has a noticeable effect on adsorption of polymer molecules to a solid interface whereby the most common outcome is that polymer adsorption is reduced.8,20 This most likely explains the experimental results shown in Figure 8, where, in the presence of Tween 80, the effectiveness of CAP Adp 0.33 and CAP Adp 0.85 as growth rate inhibitors decreased drastically. The reduction in polymer adsorption in the presence of a surfactant has been attributed to the formation of polymer−surfactant aggregates in solution.20 Interactions between polymers and nonionic surfactant are usually very weak, but interactions could occur if a sufficiently hydrophobic polymer is used, as in the current study.1,59 Thus, the decrease in effectiveness of the cellulose polymers in the presence of surfactants can be most likely attributed to a decrease in interactions between the crystallizing solute surface and the polymer molecules brought about by the presence of the surfactant. This observation is clearly important for amorphous formulations where surfactants are often added as plasticizers to aid in manufacturing of the solid dispersion.60

removing this as a potential hydrogen bonding group, leaving only a limited number of hydroxyl groups. Favorable electrostatic interactions are unlikely, since the presence of an ionized carboxylic acid group will lead to unfavorable charge− charge repulsion between the monomer units of the polymers in solution. Therefore, hydrophobic interaction was further investigated as the main interactive force between the polymer combinations. It is well-known that interactions between hydrophobic groups in water are promoted by the presence of water structuring salts. It has been argued that the salt enhances hydrophobic interactions by making the solvent more polar.47,52 Hence, when the solvent ionic strength is increased by the addition of salts, hydrophobic groups on the polymer chain will associate more strongly with other hydrophobic groups. On the basis of this reasoning, it is expected that stronger interpolymer interactions will be formed at higher ionic strengths, which could lead to an increase in effectiveness of the polymer/polymer combination by potentially increasing the adsorption of the resulting interpolymer complex to the surface of the crystallizing solid through hydrophobic interactions. The aforementioned expectations are in general supported by the results of this study. The effectiveness of the polymer combinations investigated decreased at lower ionic strength (Figure 6), suggesting that hydrophobic interactions are promoted at higher ionic strengths, where the polymer combinations are more effective. Interactions between the crystallizing solid and polymer complexes at the solid−liquid interface may also be attributed to hydrophobic interactive forces.31 Hydrophobic interactive forces are likely to make a significant contribution to adsorption of a polymer; stronger drug−polymer interactions will be formed at higher ionic strengths, which could lead to an increase in effectiveness of the polymer complexes. However, similar to the case of individual polymers,31 for the formed interpolymer complex to be effective, it should have a hydrophilic/hydrophobic balance to drive adsorption to a crystal surface. Hence, if a polymer is very hydrophobic, it is more likely to interact more favorably with other polymer molecules in solution to form a very hydrophobic interpolymer complex, which may not adsorb or, if it does, will not form very extensive interactions with the solid− solvent interface. This line of reasoning has also been proposed by Yu et al. (1996)6 and is consistent with the results in this study where the more hydrophobic polymer combinations did not show synergistic effects. In the area of solubility enhancement of poorly water-soluble drugs, it is of considerable interest to determine whether additive combinations can be used to better maintain supersaturation for extended time periods in the presence of crystal seeds that may be present in the formulation; it has been observed previously that it is very difficult to prevent desupersaturation with single additives in the presence of crystal seeds at high supersaturations.38,39 At concentrations corresponding to the amorphous “solubility” of ritonavir (∼20 μg/mL), the most effective polymer combination (CAP Adp 0.85/Pn-IPAAmd) is able to reduce the crystal growth rate of ritonavir by a factor of ∼3, a much better reduction than that for either of the individual additives (Table 5). Furthermore, at the lowest supersaturation investigated in this study (S of 3.8), crystal growth is completely inhibited by this polymer combination, which may be of relevance for inhibition of Ostwald ripening in the context of nanoparticle stabilization. This result suggests that polymer combinations should be more extensively investigated as a means to improve the stabilization

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CONCLUSIONS In this study, the effect of polymer/polymer and polymer/ surfactant combinations on crystal growth was investigated. The pairing of two moderately hydrophobic polymers or a moderately hydrophobic polymer with a more hydrophilic synthetic polymer resulted in additional reductions in crystal growth rate relative to each individual polymer. The generally improved effectiveness of the cellulose polymer pairs in inhibiting crystal growth was attributed to the formation of polymer−polymer hydrophobic interactions. In contrast, the 6058



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(7) Löfroth, J. E.; Johansson, L.; Norman, A. C.; Wettström, K. Interactions between surfactants and polymers I: HPMC. Prog. Colloid Polym. Sci. 1991, 84, 73−77. (8) Duro, R.; Souto, C.; Gómez-Amoza, L.; Martínez-Pacheco, R.; Concheiro, A. Interfacial adsorption of polymers and surfactants: Implications for the properties of disperse systems of pharmaceutical interest. Drug Dev. Ind. Pharm. 1999, 25, 817−829. (9) De Martins, R. M.; Da silva, C. A.; Becker, C. M.; Samios, D.; Chirstoff, M.; Bica, C. I. Interactions of (hydroxypropyl) cellulose with anionic surfactants in dilute regime. Colloid Polym. Sci. 2006, 284, 1353−1361. (10) Konno, H.; Handa, T.; Alonzo, D. E.; Taylor, L. S. Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur. J. Pharm. Biopharm. 2008, 70, 493−499. (11) Matteucci, M. E.; Brettmann, B. K.; Roger, T. L.; Elder, E. J.; Williams, R. O.; Johnston, K. P. Design of potent amorphous drug nanoparticles for rapid generation of highly supersaturated media. Mol. Pharmaceutics 2007, 4, 782−793. (12) Simonelli, A. P.; Mehta, S. C.; Higuchi, W. I. Inhibition of sulfathiazole crystal growth by polyvinylpyrrolidone. J. Pharm. Sci. 1970, 59, 633−638. (13) 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. 2009, 27, 608−618. (14) Dai, W. G.; Dong, L. C.; Shi, X. F.; Nguyen, J.; Evans, J.; Xu, Y. D.; Creasey, A. A. Evaluation of drug precipitation of solubilityenhancing liquid formulations using milligram quantities of a new molecular entity (NME). J. Pharm. Sci. 2007, 96, 2957−2969. (15) Raghavan, S. L.; Trividic, A.; Davis, A. F.; Hadgraft, J. Crystallization of hydrocortisone acetate: influence of polymers. Int. J. Pharm. 2001, 212, 213−221. (16) Corrigan, O. I.; Healy, A. M. Surfactants in pharmaceutical products and systems. Encyclopedia of Pharmaceutical Technology, 3rd ed.; Informa Healthcare: 2006. (17) Vasconcelos, T.; Sarmento, B.; Costa, P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discovery Today 2007, 12, 1068−1075. (18) Goddard, E. D. Polymer/surfactant interaction. J. Soc. Cosmet. Chem. 1990, 41, 23−49. (19) Nahringbauer, I. Polymer-surfactant interaction as revealed by the time dependence of surface tension. The EHEC/SDS/water system. Langmuir 1997, 13, 2242−2249. (20) Duro, R.; Souto, C.; Gómez-Amoza, J. L.; Martínez-Pacheco, R.; Concheiro, A. Cellulose ethers-polysorbate 80 interactions. Implications on the stability of pyrantel pamoate suspensions. Chem. Pharm. Bull. 1998, 46, 1421−1427. (21) Wesley, R. D.; Cosgrove, T.; Thompson, L. Structure of polymer/surfactant complexes formed by poly(2-(dimenthylamino)ethyl methacrylate) and sodium dodecyl sulfate. Langmuir 2002, 18, 5704−5707. (22) Won., D.-H.; Kim, S.-K.; Lee, S.; Park, J.-S.; Hwang, S.-J. Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process. Int. J. Pharm. 2006, 301, 199−208. (23) Dannenfelser, R.-M.; He, H.; Joshi, Y.; Bateman, S.; Serjuddin, A. T. M. Development of clinical dosage forms of poorly water soluble drug I: Application of polyethylene glycol-polysorbate 80 solid dispersion carrier system. J. Pharm. Sci. 2004, 93, 1165−1175. (24) El-Bary, A. A.; Kassem, M. A. A.; Foda, N.; Tayel, S.; Badawi, S. S. Controlled crystallization of chorpropamide from surfactant and polymer solutions. Drug Dev. Ind. Pharm. 1990, 16, 1649−1660. (25) Lu, G. W.; Hawley, M.; Smith, M.; Geiger, B. M.; Pfund, W. Characterization of a novel polymorphic form of celecoxib. J. Pharm. Sci. 2006, 95, 305−317. (26) Kumar, S.; Chawla, G.; Bansal, A. K. Role of additives like polymers and surfactants in the crystallization of mebendazole. Yakugaku Zasshi 2008, 128, 281−289. (27) Osada, Y. Equilibrium study of polymer-polymer complexation of poly(methacrylic acid) and poly(acrylic acid) with complementary

polymer/surfactant combinations investigated accelerated the crystal growth rate, thus negating the inhibitory impact of the polymer. This was attributed to a decrease in interactions between the surface of the crystallizing solute and polymer molecules because of the presence of surfactant molecules. Knowledge of the effect of additive combinations on crystal growth for a given compound would be beneficial when choosing excipients to stabilize high energy amorphous and nanoparticulate systems. By carefully selecting additive combinations, it may be possible to substantially delay crystal growth at relevant supersaturations while optimizing formulation properties.

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ASSOCIATED CONTENT

S Supporting Information *

SEM micrographs of seed crystals grown at initial S of 7.6 and 15.4 in the absence and presence of CAP Adp 0.85, PnIPAAmd and CAP Adp 0.85/Pn-IPAAmd (Figure S1 − S3); (2) particle size distribution of seed crystals before and after crystal growth experiment; (3) Unseeded desupersaturation profile of ritonavir in the absence of polymer. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*(L.S.T.) Address: Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, USA. Tel: +1-765-496-6614; fax: +1-765-494-6545; e-mail: lstaylor@ purdue.edu. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the National Science Foundation for their financial support through grant DMR-0804609. Pfizer Inc. is acknowledged for a providing fellowship for G.A.I. We also thank Xuanhao Sun of the Life Sciences Microscopy Facility of Purdue University for performing SEM analyses.

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REFERENCES

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Effect of Binary Additive Combinations on Solution Crystal Growth of

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