Evaluation of Milling Method on the Surface Energetics of Molecular

Oct 23, 2012 - Crystallographic calculations were performed using Materials Studio (Accelrys, San Diego, CA, 2008; ver. 4.4). ... Subsequently, these ...
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Evaluation of Milling Method on the Surface Energetics of Molecular Crystals Using Inverse Gas Chromatography Paul E. Luner,*,†,§ Yan Zhang,‡ Yuriy A. Abramov,§ and M. Teresa Carvajal*,‡,∇ †

Boehringer Ingelheim Pharmaceuticals Inc., Pharmaceutical Research & Development, 900 Ridgebury Road, Ridgefield, Connecticut 06877-0368, United States ‡ College of Pharmacy, Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States § Pfizer Inc., Pharmaceutical R&D, Eastern Point Road, Groton, Connecticut 06340, United States ∇ Agricultural and Biological Engineering, Purdue University, 225 South University Street, West Lafayette, Indiana 47907-2093, United States S Supporting Information *

ABSTRACT: The objective of this study was to determine whether high shear wet milling (HSWM) has an impact on the surface properties of model pharmaceutical compounds compared to dry milling (DM, impact milling). The bulk and surface properties of milled samples were characterized by solidstate methods (XRPD, TGA, DSC, microscopy) and inverse gas chromatography (IGC). The bulk properties of both model compounds (succinic acid and sucrose) were unaffected by milling method. For succinic acid, the solvents methyl tert-butyl ether (MTBE) and isopropyl acetate resulted in small changes in surface properties of the powders relative to the DM material. In HSWM, the dispersive surface free energy of sucrose depended on the solvent polarity, changing from 55 to 71 to 90 mJ/m2, for hexane, MTBE, and ethanol, respectively, whereas the DM material had a value of 44 mJ/m2. The surface free energy difference between DM and HSWM was not attributable to specific solvent adsorption and was shown to be caused by a combination of attrition in the presence of solvent. Analysis of the slip planes and σ surfaces for the compounds supported the nature of particle attrition and its impact on surface energics. Assessment of surface energetics may be used to establish consistency of drug substance surface characteristics when previously established milling processes are modified.

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INTRODUCTION The surface interactions and surface properties of organic molecular crystals are very important in pharmaceutical formulation science.1 Modification of surface properties may provide improved powder performance in active pharmaceutical ingredients (APIs) and excipient interactions, such as powder mixing, segregation, wet granulation, suspension formation, and film coating.1 Surface interactions can also play a role in drug physical stability by influencing the moisture adsorption behavior of a drug substance.2−4 It is wellestablished that milling affects the surface energy of pharmaceutical materials.5−8 Dry impact or attrition milling is an ubiquitous technique for particle size reduction of APIs and remains a reliable means of particle size reduction for pharmaceutical solids.9 High shear wet milling (HSWM) is a widely used milling technique and is different than attrition milling in the dry state because particle fracture occurs while the particles are entrained in an antisolvent medium.10 Consequently, newly fractured and defected surfaces are in contact with a saturated API solution during wet milling and have the opportunity to anneal or undergo Ostwald ripening in © 2012 American Chemical Society

contrast to dry milling. HSWM can produce materials in similar particle size regimes as dry milling, although the particle size reduction limits for HSWM are typically higher than those for dry-milling methods. HSWM has the advantage of facile containment and isolation from airborne powder during particle size reduction and is encountering increased use in the pharmaceutical industry.10 API material properties can have a significant impact on the difficulty of development of drug products.11−13 Additionally, it has been reported that particle engineering methodology used for API manufacture can significantly impact drug product formulation and performance affecting the quality attributes of a material.12 However, the impact of wet milling on the surface properties of organic crystals relative to dry milling has not been thoroughly characterized. A greater understanding of the potential influence of different milling methods on the surface properties of APIs would be beneficial for selecting the appropriate milling Received: June 9, 2012 Revised: September 5, 2012 Published: October 23, 2012 5271

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microscopy (SEM), particle size distribution analysis, dynamic vapor sorption (DVS), and surface analysis by inverse gas chromatography (IGC). XRPD. The patterns were collected on a Bruker D5000 diffractometer (Madison, WI) using Cu radiation (1.54056 Å). The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set at 1 mm, and the receiving slit was set at 0.6 mm. Diffracted radiation was detected by a Kevex PSI detector. A θ-2 θ continuous scan at 2.4°/min (1 s/0.04° step) from 3.0 to 40° 2θ was used. An alumina standard was analyzed to check the instrument alignment. Data were collected and analyzed using Bruker Axis software, version 7.0. Samples were prepared by packing them in a quartz holder. TGA. Solvent loss and thermal stability were assessed by a TA Q5000 (New Castle, DE). The powder samples were heated from room temperature to 350 °C at a rate of 10 °C/min under N2 at a flow rate of 50 mL/min. The sample size for each measurement was approximately 15 mg. DSC. Data were collected on a TA Q1000 (New Castle, DE) to study thermal events up to the melting. About 5 mg of material was sealed in a hermetic pan with a lid, which was manually punched with a hole in the center for each measurement. The samples were heated from room temperature to 250 °C at a rate of 10 °C/min in a dry N2 atmosphere at a flow rate of 20 mL/min. PLM. The morphology of the particles was directly visualized by microscopy. The samples were prepared by placing a small amount of powder on a slide with silicon oil and observed at magnifications of 4×, 10×, 25×, and 40×. SEM. Samples were examined using a Joel JSM 5800 scanning electron microscope (Tokyo, Japan). SEM samples were prepared by dispersing the powders onto Al stubs with an adhesive mount and sputter-coating with gold palladium. The electron beam was operated at 10 kV. Particle Size Analysis. The distributions of the powders were determined using a Sympatec Helos/Rodos laser diffraction particle size analyzer (Sympatec Inc., NJ) with dry powder dispersion capability. The powder dispersion pressure was set as 0.20 bar, with a 80% feed rate. The measuring range was up to 1750 μm, and the cycle time was 10.0 ms. Water Sorption Studies. Data were collected using a VTI SGA 100 (VTI Corporation, Hialeah, FL). Surface Energetics. Inverse gas chromatography (IGC) was used to measure the dispersive surface free energy and specific component of the free energy of adsorption of probe molecules for the powder samples. IGC tests were conducted using a commercial IGC system (iGC, Surface Measurements Systems Ltd., Alperton, Middlesex, U.K.). Approximately 2 g of the powders was packed and weighed in a silanized glass column (340 mm length and 4 mm internal diameter), using an automated tapper for 10 min subsequent to filling the glass column. Before IGC measurement, samples were equilibrated with dry helium at 303 K and 0% RH, for 4 h in the system. Helium (ultra-highpurity) was used as the carrier gas, and methane was used to determine the dead volume of each column. The vapor probes used included a linear hydrocarbon series (hexane, heptane, octane, nonane, and decane) and a polar series (ethyl acetate, acetonitrile, nitromethane, 1,4 dioxane, formamide, and acetone). The probes were injected separately at 303 K at an injection pressure of 0.2 p/p0 for succinic acid, and 0.05 p/p0 for sucrose, except where noted. A flame ionization detector was used. IGC Data Analysis. The primary experimental parameter measured in IGC is the net retention volume (Vn). Vn is related to the surface partition coefficient (K s), defined as the ratio between the concentration of the probe in the stationary phase and in the mobile phase, respectively

process to optimize the drug product performance characteristics of an API. Inverse gas chromatography (IGC) at infinite dilution is an established technique in the pharmaceutical sector14,15 as well as in other fields16,17 for the characterization of the surface properties of powders. The main utility of IGC is identifying the batch-to-batch variability where bulk techniques do not resolve differences.1,18 In this study, IGC, along with particulate and bulk characterization techniques, has been used to characterize differences between dry impact milled API and HSWM API conducted in different suspending media (solvents). The two model compounds (sucrose and succinic acid) were selected based on (i) the ability to obtain commercially available starting material sufficiently large enough to allow significant particle size reduction and (ii) one material having the propensity to disorder during milling (sucrose) and the other retaining crystallinity upon extensive comminution (succinic acid). Crystallographic modeling and interaction energy calculations have been performed for selected surfaces of the crystals as a preliminary means to gain insight into the experimentally observed results.

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EXPERIMENTAL SECTION

The model compounds selected for milling in this study were succinic acid and sucrose. Succinic acid (β form) was obtained from SigmaAldrich (SigmaUltra grade, >99.0%). Sucrose was obtained from J.T. Baker (Baker analyzed, ACS reagent grade). The series of organic solvents used as IGC nonpolar probes (all purities > 99%) consisted of hexane (EMD Chemicals), heptane (Sigma-Aldrich), octane (Fluka), undecane (Sigma-Aldrich), and dodecane (Sigma-Aldrich). The polar probes used, all obtained from Sigma-Aldrich (all purities > 99%), were ethyl acetate, acetonitrile, nitromethane, 1,4-dioxane, formamide, and acetone. The solvents used for HSWM were methyl tertiary butyl ether (MTBE, Burdick & Jackson, >99.9%), isopropyl acetate (Acta Aesar, >99%), hexane (EMD Chemicals, HPLC grade), and ethanol (Pharmaco-AAPER, ACS/USP grade). Milling Processes. High shear wet milling was performed using a Silverson L4RT-A mill (East Longmeadow, MA). Either of two rotor heads was used; a square-hole head or a round-hole head. In each milling operation, 15 g of material was placed into 200 mL of fluid in a three-neck flask. The milling head was positioned through the middle hole of the flask about 5 mm above the flask bottom. The milling speed was set at 10 000 rpm and the milling durations were 10 and 15 min for succinic acid and sucrose, respectively. These milling times represented the point at which no further particle size reduction was observed by means of an FBRM (focused beam reflectance measurement) online particle size measurement probe. After milling, the product was filtered and dried in a vacuum oven for 24 h at 40 °C. In experiments where unmilled or previously processed material was washed with solvents, a similar mass of powder was gently stirred in the solvent for 15 min, decanted, and then dried. An impact mill (MF 10 grinder drive with an MF 10.2 impact grinding head; Ika, Inc., Wilmington, NC) was used for dry milling, where a 20 g sample of the powder was gradually fed into the receiver chamber and collected from the bottom of the chamber. The milling speed was set at 6500 rpm, and screens with hole diameters of either 0.25, 0.5, or 1.0 mm were used for milling succinic acid. For sucrose only, the 0.25 mm screen was used. Cryogenic milling was performed on a 3 g sample of sucrose using a SPEX CertiPrep 6750 cryogenic impact mill (Metuchen, NJ). During milling, the process was carried out as alternate cycles consisting of 2 min of milling and 1 min of cooling after precooling for 5 min. The total milling time was 30 min. All milled samples were stored in a desiccator at ambient temperature. Characterization. The as-received crystals and milled powders were characterized using X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), polarized light microscopy (PLM) and scanning electron

K s = Vn /m· A sp

(1)

where m is the weight of the sample in the column and Asp is the specific surface area of the sample in the column. From Ks, the standard free energy of adsorption (−ΔGA) can be derived 5272

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were compared to the unmilled material as well as the theoretical powder X-ray diffraction patterns generated from the crystal structures of the α and β forms. Neither milling operation resulted in significant deviation from the β form, although a small peak at 22° 2θ was noted in all the samples, including the starting material, indicating some initial minor polymorphic impurity. However, no additional transformation was noted as a result of milling (Figure 1). Additionally,

(2)

where Psg is the standard vapor state (101 kN m−2) and P is the standard surface pressure (0.338 mN m−1). Dispersive and specific interactions are considered to contribute independently to the adsorption of the probe molecules and represent the nonpolar and polar properties of the surface, respectively. Adsorption of nonpolar probes (e.g., alkanes) results from dispersive interactions only, whereas polar probes are capable of both dispersive and specific acid−base interactions with the powder surface. Following the method of Schultz et al.,16 who derived the equation

RT lnVn = a(γ1d)1/2 2N (γs d)1/2 + C

(3)

where N is Avogardro’s number and γsd is the dispersive component of the surface free energy of the solid sample; γsd can be calculated from the gradient of the straight line produced by the alkanes. The specific component of the surface free energy of adsorption (−ΔGAsp) is determined from the vertical distance between the alkane reference line and the polar probe of interest.16,19 A preliminary assessment of whether the probes used for sucrose (wet-milled material) satisfied the infinite dilution assumption was carried out by inspecting the linearity of the isotherms in the region of the chosen injection pressure. The points on the isotherm corresponding to the injection pressures used for all solvents were sufficiently low enough to ensure adherence to the Henry’s Law assumption implicit for infinite dilution experiments. Additionally, the injection pressures used here were similar to those routinely used for API analysis using the infinite dilution method.6,20 IGC and characterization measurements were conducted within several days of sample preparation. Replicate measurements on packed columns were conducted over a period of several weeks. Solvent Wash Experiments. Sucrose was examined to assess the possible influence of residual solvent or surface modification of the powders by the solvent on the IGC results. The sucrose powder samples that had not previously contacted solvent were washed with either MTBE or hexane. This was done by dispersing the sucrose powder, either unmilled or dry-milled, in the solvents used for HSWM, treating them in a similar manner, but excluding the particle attrition process in the solvent. The washed powders were subsequently dried and then analyzed by IGC. Computational Analysis. Crystallographic calculations were performed using Materials Studio (Accelrys, San Diego, CA, 2008; ver. 4.4). The crystal structure data for sucrose and succinic acid (ref codes SUCROS04 and SUCACB08, respectively) were obtained from the CCDC.21 The equilibrium growth morphologies in the gas phase were calculated using the Morphology module with the COMPASS force field.22 For estimation of the interaction of liquids with specific crystal surfaces, the unrelaxed vacuum slabs were constructed via bulk primitive cells containing periodic units of the selected dominant faces of the crystal separated from each other by a 40 Å vacuum spacing. The screening surface charge densities (σ surfaces) were calculated for these surfaces using the COSMO-RS approach23 at the PBE/DNP/ COSMO level of theory24,25 as implemented in the DMol3 module in Materials Studio 4.4 (Accelrys). Subsequently, these σ surfaces were utilized to calculate free energies, Gsolv(hkl), of unit cells of dominant crystal faces in different liquid solvent media using COSMOtherm software (Eckert, F.; Klamt, A. COSMOtherm, version C2.1, release 01.09; COSMOlogic GmbH & Co. KG: Leverkusen, Germany, 2009). Gsolv(hkl) values were normalized per one molecule in the unit cell.

Figure 1. Overlay of X-ray powder diffraction patterns for (a) unmilled, (b) dry-milled, and (c) wet-milled original succinic acid. Inset shows an overlay of the DSC scans for the same samples.

RESULTS Succinic Acid. It is known that succinic acid has two polymorphic forms, the room-temperature stable β form and a metastable α form. During ball milling and jet milling, the β form can partially convert to the α form.26 The β form can be distinguished by a “fingerprint” peak at 2θ = 20°, whereas the pattern for the α form shows a distinct peak at 22° 2θ. The XRPD patterns of the dry and HSWM succinic acid samples

Visual examination of SEM images reveals the acicular nature of the milled powders (Figure 2) and indicates that each milling process results in a similar attrition behavior. The SEMs show that the ends of the dry-milled crystals are sharp, whereas the wet-milled crystals are rounded. Additionally, the SEMs (Figure 2) reveal very small particles attached on the surface of drymilled crystals; however, the surfaces of wet-milled crystals are fairly clean. Images at 10 000× show the detail of the particle surface. It can be seen that all of the milled samples have very

thermal analysis using DSC demonstrated no significant differences between milled and original powders (Figure 1). The D50 of these samples indicate that, under the conditions employed, dry milling resulted in a smaller particle size, although the fines fractions as represented by D10 were similar (Table 1). Table 1. Particle Size Data for Succinic Acid and Sucrose material

milling condition

succinic acid

HSWM

sucrose

dry mill HSWM

dry mill

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isopropyl acetate MTBE 0.25 mm screen hexane MTBE ethanol 0.25 mm screen

D10 (μm)

D50 (μm)

7.7 10.4 8.8 25.2 7.4 7.2 16.7

55.6 63.4 27.8 89.0 37.3 33.3 46.2

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Figure 2. SEM images of succinic acid: (a) unmilled particles, (b) dry-milled powder, (c) isopropyl acetate wet-milled powder, and (d) MTBE wetmilled powder. Magnifications are shown in the individual micrographs.

the milled samples, but the overall balance of acid/base character does not change greatly relative to the starting material. Sucrose. Wet milling and dry milling were conducted on sucrose crystals analogous to the succinic acid milling experiments. The XRPD patterns (Figure 4) of the HSWM and DM samples did not show a noticeable peak position shift relative to the unmilled crystals; differences in the patterns were attributable to the peak intensity difference and preferred orientation due to the size of the unmilled crystals. Comparison with the theoretical XRPD pattern from the single-crystal structure of sucrose (data not shown) showed that, after milling, sucrose retains its crystal form and crystallinity (to the extent that can be determined by visual inspection of the XRPD patterns). Thermal analysis demonstrated no significant differences in milled versus the unmilled sucrose (Figure 5). There was no indication of a Tg present in the DSC scans of the milled samples, and the melting onsets were all similar to those of the unmilled reference state, indicating no apparent change in crystallinity. A broad and minor endotherm at approximately 150 °C was observed in all the samples tested, and the appearance of this feature in purified sucrose has been previously reported30 and may be related to the appearance of a recently discovered concomitant conformational poly-

smooth surfaces and there were no gross visible differences among these samples. All of the milled samples have a higher dispersive surface free energy than the unmilled crystals (Figure 3a; see also the Supporting Information). The dispersive surface free energy of succinic acid wet-milled with MTBE is slightly higher than that of the dry-milled sample. The interactions provided by polar probes27−29 on the solid surface are represented by the specific component of the surface free energy of adsorption (−ΔGAsp). The polar probes used to determine −ΔGAsp were ethanol (amphoteric), ethyl acetate (strongly basic), and 1,4-dioxane (basic/amphoteric). In assessment of the unmilled samples, the strongly acid probe (chloroform) was not retained sufficiently. This indicates weak interaction with the surface, and it can be inferred that the surface is acidic in nature. The amphoteric probes interact with the samples to an increasing degree from unmilled and dry-milled to HSWM MTBE, but the relative balance of interaction is similar across the three IGC probes (Figure 3b). Only the sample HSWM in isopropanol shows a shift in the relative magnitude of interaction among each of the probes. This may indicate that the nature of the resultant facets formed during milling and their surface chemistry are different from both the dry-milled and the MTBE wet-milled samples. The increase in −ΔGAsp indicates a more energetic surface of 5274

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Figure 4. Overlay of X-ray powder diffraction patterns of sucrose (a) unmilled, (b) dry-milled, (c) HSWM hexane, and (d) HSWM MTBE. The larger particles present in the unmilled material result in some preferred orientation effects.

Figure 3. (a) Dispersive surface free energy of milled and unmilled succinic acid. Injection pressures were p/p0 = 0.2 for each IGC probe molecule. (b) Specific component of the free energy of adsorption of probe molecules for unmilled and milled succinic acid. Key for IGC probe molecule: (red) ethanol, (blue) ethyl acetate, and (black) dioxane. Injection pressures were p/p0 = 0.2 for each IGC probe molecule.

morph.31,32 However, DSC results showed that this feature was present and consistent in the unmilled and treated sucrose samples. Values of D50 (Table 1) show that wet milling in ethanol or MTBE produced the smallest particle size and wet milling in hexane resulted in the highest particle size (D50 ∼ 90 μm). The PLM micrographs (not shown) confirmed the SEM data (Figure 6) that the unmilled particles have a regular prismatic shape. After milling, they were fractured into much smaller particles lacking a distinct or uniform morphology. There were no distinct observable visual differences in morphology observed relative to application of the different milling techniques to sucrose. Under polarized light, the samples were highly birefringent, indicating no evidence of bulk amorphous content. The low-magnification SEM images

Figure 5. Overlay of DSC scans of unmilled and milled sucrose samples. Inset shows the expanded region of 100−200 °C. Key: (a) unmilled, (b) dry-milled, (c) wet-milled with hexane, and (d) wetmilled with MTBE.

(100× and 1500×) show that both dry-milled and wet-milled sucrose from different solvents generate small particles with a relatively narrow distribution and irregular shapes. The surfaces of the milled particles are quite smooth, as seen from the highmagnification (10 000×) SEMs. No agglomeration was obvious in the samples. It was anticipated that, in the drying phase after wet milling, as solvent is evaporated out of the system, the sucrose dissolved in the solvent could crystallize out as very fine particles and deposit on the surface of milled particles. 5275

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Figure 6. SEM images of sucrose: (a) unmilled, (b) dry-milled powder, (c) wet-milled with hexane, (d) wet-milled with MTBE, and (e) wet-milled with ethanol. Magnifications are shown in the individual micrographs.

fraction was not correlated with the increase in surface energy for the various milled samples. The increase in surface energy upon milling observed in this work is consistent with that reported by Rousett et al.33 that IGC determined dispersive surface free energy values increased from 30 to 37 mJ/m2 for granulated and jet-milled sucrose, respectively. The dispersive surface energies of the milled samples were also compared to that of an amorphous sample generated by cryomilling. The cryomilled sample was assessed by several methods (XRPD and dynamic moisture vapor sorption), both of which indicated conversion to a partially amorphous state (see the Supporting Information). Although bulk quantification of the amorphous content was not undertaken, based on previous milling studies of sucrose,34,35 it was assumed that the extent of amorphous content in the sample extended beyond

However, there does not appear to be direct evidence to support this hypothesis based on the SEMs. Sucrose shows a similar trend in surface energy changes compared to the succinic acid relative to milling: for both DM and HSWM, the dispersive surface free energy increases relative to the unmilled material (Figure 7a; see also the Supporting Information). Sucrose wet-milled in ethanol showed the highest dispersive surface free energy, 90 mJ/m2, which is almost 3-fold higher than that of the unmilled particles. Wet milling performed in the other solvents (hexane and MTBE) also produced material with a higher surface free energy (55 and 71 mJ/m2, respectively) than the unmilled material (34 mJ/m2). Dry milling also altered the dispersive surface free energy of the original particles, increasing it to 43 mJ/m2. For sucrose, the D10 varied depending on the milling method, but the fines 5276

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experiments that mimicked the solvent (either hexane or MTBE) exposure of the wet milling process without the particle size reduction taking place in the presence of solvent and was performed with either unmilled sucrose or sucrose that had been previously dry-milled. The dispersive surface free energy of sucrose crystals exposed to solvent was similar to that of the unwashed material (unmilled or dry-milled, respectively). The dispersive surface free energy of these treated samples was significantly lower than that of the HSWM samples from either solvent (Figure 8a). The behavior was observed for washing

Figure 8. (a) Effect of solvent washing on dispersive surface energy of unmilled and dry-milled sucrose particles relative to unwashed and wet-milled. Key: (red) untreated, (green) MTBE washed, (blue) hexane washed, (black) wet-milled in hexane, and (grey) wet-milled in MTBE. IGC probe molecule injection pressures for samples are indicated in graph: (∗) p/p0 = 0.05; (∧) p/p0 = 0.2. (b) Effect of MTBE washing on the specific component of the free energy of adsoprtion for unmilled and dry-milled sucrose particles relative to untreated and wet-milled. Key: (black) unmilled, (red) unmilled and washed, (green) dry-milled, (yellow) dry-milled and washed, and (blue) wet-milled. IGC probe molecule injection pressures were p/p0 = 0.2.

with hexane or MTBE. Additionally, the relative changes in the specific component of the free energy of adsorption for the acidic and basic probes followed the same trend (Figure 8b). Theoretical Morphology and Surface Analysis. As an initial means to probe the rationale for these surface energy behaviors relative to milling, both the equilibrium growth morphology and an analysis of the slip planes in sucrose and succinic acid crystals were calculated. The growth rate of the face according to the growth morphology model is proportional to its attachment energy, Eatt.37,38 The attachment energy is defined as the energy released on attaching a new layer of molecules to a growing crystal face. Faces with the smallest absolute attachment energies are the slowest growing and, therefore, have the highest surface area and most morphological importance. In addition, the corresponding crystallographic planes are the most weakly attached to each other inside the crystal. Therefore, it is assumed that the smallest absolute attachment energies also define the most probable slip/cleavage planes that are more likely to be exposed from crystal fracture.7,39 Once the dominant morphology facets and slip/ cleavage planes were defined, these surfaces were analyzed in terms of their screening surface change densities (σ surfaces) as an indicator of the relative polarity and the way of estimation of the surface stabilization/destabilization by different solvent media. Inspection of the packing motifs and hydrogen-bonding patterns in succinic acid reveal that the molecules interact with each other by strong hydrogen bonding to form molecular

Figure 7. (a) Dispersive surface free energy of milled and unmilled sucrose. (b) Specific component of the free energy of desorption of probe molecules for milled and unmilled sucrose. Key for IGC probe molecule: (red) acetonitrile, (green) nitromethane, (blue) ethyl acetate, and (black) dioxane. Injection pressures were p/p0 = 0.05 for each IGC probe molecule (cryomilled p/p0 = 0.2).

just the surface amorphous content.36 The cryomilled sample had a dispersive energy of 68.5 mJ/m2, which fell between that of the dry-milled powder and the material wet-milled in ethanol. After wet milling or dry milling, the polar crystal surfaces became more energetic, as indicated by the general increase in −ΔGAsp (Figure 7b; see also the Supporting Information). All of the wet-milled samples had −ΔGAsp values greater than the dry-milled sample. The polar probes used to determine −ΔGAsp were acetonitrile (amphoteric base), ethyl acetate (∼monopolar basic), 1,4-dioxane (amphoteric base), and nitromethane (amphoteric). All of these probe molecules interacted favorably and indicate a general trend toward acidic character for the surface. Overall, the milling treatment did not alter the acidic/ basic balance and the exposure of acidic/basic surface sites due to particle fracture was relatively uniform. There was a trend toward an increase in either exposure or strength of those interacting sites relative to unmilled sucrose for the various milling treatments. Impact of Solvent Exposure. The potential role of the solvent in altering the surface energy of sucrose was assessed by 5277

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formed by these planes are the weakest in the crystal. The σsurface analysis (Figure 9) for succinic acid for these planes shows similarity in their polarity profile, and the full extent of polarity is not fully exhibited, as represented by the lack of strong red or blue color as indicators of donor/acceptor character. Sucrose is characterized by a 3D network of strong hydrogen bonds, and the smallest Eatt for the weakest interacting planes is −30 kcal/mol. The family of the planes displaying the weakest attachment energies, {100}, {001}, and {110}, intersects the unit cell in the different directions (Figure 10). Consequently, crystal fracture and splitting along these planes should produce irregularly formed crystals during milling. This is consistent with the observed particle morphology of the milled samples (Figure 6). The σ surfaces of these dominant planes show significant variation in polarity (Figure 11), and it is partially a result of the unsatisfied hydrogen bonding in the cleaved surfaces.

layers along the families of crystallographic planes {111} and {020} (Figure 9). This is reflected in the attachment energies of

Figure 9. Planes (020) (a) and (111) (b) containing layers of succinic acid molecules connected to each other by a network of strong hydrogen bonds and the corresponding σ-screening surfaces of the planes (c, d). For the σ-screening surfaces, color distribution is from blue (represents donor) to red (represents acceptor), with green representing hydrophobic features. Brown defines the crystal plane.

the planes intersecting these layers, which were all lower than −40 kcal/mol. The interaction between the layers that does not involve hydrogen bonding is much weaker (Eatt = −18 kcal/ mol). Thus, the (111) and (020) planes containing the molecular layers are the slowest-growing planes, which define the succinic acid morphology. The observation in the SEMs (Figure 2) that succinic acid maintains its characteristic needlelike morphology upon milling is reinforced by the crystallographic findings that indicate that the crystal will likely be split along the {111} and {020} planes, forming smaller needles (Figure 10), because the interactions between the surfaces

Figure 11. Morphology planes (100) (a) and (001) (b) of the sucrose crystal and the corresponding σ-screening surfaces of the planes (c, d). For the σ-screening surfaces, color distribution is from blue (represents donor) to red (represents acceptor), with green representing hydrophobic features. Brown defines the crystal plane.

As an additional means to assess the relationship of milling solvent to the observed surface energy change for wet-milled sucrose, the σ surface formed from the (001) plane was analyzed for its interaction with hexane, MTBE, and ethanol. The calculated values of surface free energies in the solvent media, ΔGsolv (001), were normalized to the value for hexane. According to this normalization, the obtained values of the relative change in ΔGsolv(001) were 0, −7.7, and −8.3 kcal/mol for hexane, MTBE, and ethanol, respectively, and indicate a qualitative trend for greater stabilization of the sucrose plane by increasing polarity of the milling solvent. In contrast, the variation of similarly calculated ΔGsolv values for the succinic acid morphology plane (020) in the same three solvents and in isopropanol do not exceed 0.4 kcal/mol, indicating a reduced

Figure 10. (a) Depiction of the family of the slowest-growing planes, {111} and {020}, in the succinic acid unit cell that represent the weakest interacting planes in the crystal. (b) Depiction of the family of the slowest-growing planes in the sucrose unit cell that represent the weakest interacting planes in the crystal. 5278

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in hexane. While it is clear that, in the case of sucrose, the polarity of the solvents influenced the surface energy of the particles (ethanol > MTBE > hexane), the mechanism by which the more polar solvent affected this change is not readily evident. Two possible artifacts could be responsible for the alteration in surface energetics due to solvent in wet milling. One hypothesis is that the surface energy changes due to wet milling are because solvent adsorbs onto the surface of crystals, either physically or chemically, and is not removed during drying. This could cause an alteration in the surface energy due to the probe molecules interacting preferentially with adsorbed solvent. A second hypothesis is that the solvent modifies the surface of the crystal by preferential etching or surface dissolution to a different extent with each solvent and alters the presence or proportion of functional groups on the crystal surfaces. The solvent washing experiments were used to investigate these possible causes. The impact of washing on the surface energy of organic materials has been observed in a recent study with starch,50 where differences on the surface were clearly observed and IGC was a suitable technique to detect the changes. In this work, the comparison of the surface energy data for unwashed and washed material (Figure 8) clearly indicates that the solvent washing process, whether applied to unmilled or previously fractured sucrose (drymilled), did not significantly influence the surface energy. If the solvent affected the surface by an adsorption or etching mechanism, then the solvent-exposed crystals would be expected to have values similar to those of the wet-milled samples. Consequently, solvent contact alone cannot be the only factor augmenting the surface energy in wet-milled samples. Furthermore, these results point to a combined interaction between solvent and attrition or cleavage altering the surface energetics of the wet-milled samples to a different extent than simple dry milling. It is possible that the polarity of the solvent influences the process of crack propagation and crystal cleavage through stabilization of the newly formed surface.51,52 It is known that milling can induce defects and disorder to crystalline materials and can have an impact on their surface energy.36,40 Thus, an additional hypothesis for the increase in surface energy parameters for succinic acid and sucrose as a function of milling is that amorphous material was generated and its presence is contributing to the total measurement. In the case of succinic acid, this is unlikely because the milling conditions were relatively mild and it is known that succinic acid retains almost 100% crystallinity even when ball-milled (high energy) for long periods.26 Additionally, the characterization evidence (DSC, XRPD) did not indicate any crystallinity reduction. For sucrose, moisture sorption tests for dry-milled sucrose did not exhibit any significant water uptake and subsequent expulsion of moisture indicative of amorphous content. In addition, bulk characterization showed no indication of phase transformation. Although one cannot rule out very small amorphous or disordered surface regions, it is unlikely that dry or wet milling under the conditions employed resulted in generation of amorphous content. To further probe the impact of amorphous regions on the surface energy of sucrose, the dispersive surface free energy of a cryomilled sample was measured. Although the extent of disorder was not determined quantitatively, it is reasonable to assume that the cryomilled sample had a highly defective, small particle size with altered

influence of the HSWM solvent on the succinic acid crystal surfaces.

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DISCUSSION There have been a number of investigations of the effect of milling on the surface properties of various compounds of pharmaceutical interest.6,7,14,15,40−43 Typically, the milled crystals have a higher dispersive surface free energy than the unmilled crystals (consistent with the observations in this work), and it is understood to be due to the relative increase in exposure of specific crystal planes that present different chemical groups as a result of particle size reduction and particle fracture6,7 compared to the crystal planes of the unmilled material. Changes in surface energy can also be attributed to the formation of disorder at the surface.36 This study was designed to explore the impact of wet milling compared to dry milling on the surface properties of organic crystals. The two compounds selected represent materials that demonstrate different bulk solid-state behaviors when subjected to comminution stresses. Succinic acid is a compound that does not undergo significant crystal form transformation or reduction in crystallinity during normal milling, and therefore, surface energy changes would be due to alteration in the expression or proportion of specific groups on different exposed crystal faces. Crystalline sucrose is known to partially amorphize during milling,34,44 but it does not undergo polymorphic transition during milling.45 Sucrose was selected as a model of the compound that can fracture and/or disorder during milling but has no other phase transformations. Therefore, surface energetic changes due to milling would be due to exposure of crystal faces with different surface chemistries than the original particles, the formation of amorphous surface regions, or a combination of both. Characterization of the bulk properties of the milled succinic acid and sucrose did not show evidence of reduction of crystallinity or polymorph transition. Consequently, it can be assumed that, after wet milling or dry milling, both model compounds stay in a crystalline state identical to the original particles at the bulk level. Both compounds show a trend toward increased surface energy after milling. Wet-milled samples had a consistently higher surface energy than the dry-milled sample, and this change was much more prevalent in sucrose than in succinic acid. The finding of an increased surface energy for wet milling versus dry milling is contrary to the assumption that the presence of solvent and the opportunity for defects to Ostwald ripen in wet milling would result in lowering of surface energy. Additional studies with a variety of organic crystals are needed to determine whether the effects seen can be generalized. Overall, the surface energy changes upon milling of the two compounds studied are consistent with the concept of preferential cleavage along specific planes during milling, resulting in exposure of new surfaces that reflect an alternate bulk surface chemistry. The combination of IGC analysis with molecular modeling7,14,46−48 and with crystal facet surface energy determinations49 has validated this concept. However, these various findings do not provide for a simple interpretation of why the solvent effects were seen in this study. In HSWM, it was found that the samples milled in different solvents had significant differences in surface energy. For wetmilled sucrose, it was found that the samples milled in ethanol had a higher surface energy relative to crystals milled in MTBE, and both of these samples had higher values than crystals milled 5279

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be partially a result of the similarity of the native surface arrangement of atoms and minimal impact of cleavage and exposure of crystal planes with similar atomic surface arrangements. In contrast, large changes in dispersive surface energy for unmilled relative to milled crystals and significant change in the specific component of the surface free energy can be observed, as in the case of sucrose. In HSWM, as shown in this study, the solvent system can have an unexpected and significant influence on the resultant surface energetics of the powders. It is important to note that IGC at infinite dilution used for surface energetics analysis is understood to only interrogate a subset of the energetic heterogeneity of the surface of a sample, although it has been shown that a distribution of sites is sampled and not just high-energy sites.20,56 From a practical physical standpoint, it is not known whether the sites probed by infinite dilution IGC would be those operative in determining bulk surface phenomena, such as surface adhesion. Additional techniques are being developed that employ finite dilution methodologies to probe surface energy heterogeneity15,57 and may be useful in examining the effects noted in this study under infinite dilution conditions. Nonetheless, the surface energy changes established using infinite dilution IGC in this study represent physical changes that are measurable, consistent, and characteristically related to sample treatment. The results of this study show that molecular crystals milled using different solvents in HSWM can modulate the surface energetics of the resultant particles differently than dry milling. Additional investigation into how wet milling and the solvent affect other crystalline systems relative to dry milling is of continuing interest because of the potential to alter powder performance characteristics through surface energy changes.

surface characteristics. The cryomilled material had a higher dispersive surface free energy than the unmilled as well as some of the other milled samples. The relative trend in surface energy change for materials undergoing crystalline-to-amorphous transformation is not universally consistent in the literature. There are some reports of increases in dispersive free energy upon milling for some materials,36,53 whereas other disordered materials do not necessarily display higher surface energy values than their crystalline counterparts.40,54 Nevertheless, what is of significance in the present results is that HSWM was capable of increasing the surface energy of sucrose to a greater degree than partial amorphization and the cryomilled sample did not have the highest overall surface free energy compared to the wetmilled sucrose. It is not possible based on these experiments alone to determine whether the same phenomena that govern the surface energy change from unmilled to (dry or HSWM) milled versus unmilled to cryomilled are operative. The resultant morphologies of the particles after milling for succinic acid and sucrose are consistent with the slip plane analysis that has been applied to other API-like materials.39,55 Whereas succinic acid fractures preferentially into a needle-like morphology, sucrose fractures into a shardlike, undefined morphology. On comparison of the plane interactions between succinic acid and sucrose, it is shown that sucrose has the much stronger overall level of interaction among the planes. The nature of the planes formed in sucrose indicates that the dominant morphology and slip planes, (100), (001), and (110), have unsatisfied hydrogen-bonding potential and the surface energy and polarity of these planes are relatively high. This is reflected in the corresponding σ-screening surfaces of these planes (Figure 11), and compared to succinic acid (Figure 9), the two sucrose surfaces have a greater overall difference between donor and acceptor character. This may partially explain the greater magnitude of change in the specific component of the free energy of sucrose from the unmilled to milled states compared to succinic acid. In the sucrose crystal, the greater polarity of these specific faces may result in more favorable interaction with the more polar solvents during attrition and provide a more energetically stabilized environment for the cleaved crystal surfaces. This hypothesis is supported by the trend in ΔGsolv (001) as a function of milling solvent polarity and contributes to the concept that solvent augments crystal cleavage (as described above) by preferentially stabilizing particular interfaces, facilitating the probability of fracture along those planes and causing a greater proportion of the energetically stabilized planes to be formed. Upon removal of the polar solvent, the surface may be left in a higher-energy state compared to that obtained under dry milling or wet milling with a less polar solvent. Qualitatively, there was also a highly linear correlation between particle size (as represented by D50) and the relative change in ΔGsolv (001), indicating a role for solvent interaction in facilitating fracture or milling efficiency. More detailed analysis is needed to further relate the identified crystallographic features and the proposed surface interactions to the observed experimental surface energy relationships that occur as a result of milling and their relationship to milling efficiency.

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ASSOCIATED CONTENT

S Supporting Information *

Dispersive surface energy and specific component of the free energy of adsorption for polar probes on succinic acid; dispersive surface energy and specific component of the free free energy of adsorption for polar probes on sucrose; overlay of XRPD scans for unmilled sucrose and 30 min cryomilled sample; and kinetic weight uptake plot for cryomilled sucrose held isothermally at 30 °C and 25% RH showing characteristic moisture uptake followed recrystallization and expulsion of adsorbed water. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Phone: (203)798-4955 (P.E.L.), (765) 496-6438 (M.T.C). Fax: (203)791-6197 (P.E.L.), (765) 496-1356 (M.T.C). E-mail: [email protected] (P.E.L.), tcarvaja@ purdue.edu (M.T.C). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The experimental and molecular modeling analysis portions of this work were conducted at Pfizer Inc., Groton CT. M.T.C. and Y.Z. acknowledge support from the National Science Foundation under Grant NSF-CMMI-0825994 and thank Dr. Marisol Koslowski for helpful discussions. The authors also thank colleagues at Pfizer Inc., Groton, CT, for their assistance

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CONCLUSIONS The extent of any milling effect on surface energetics will ultimately depend on the specific compound. In some cases, as exemplified by succinic acid, only minor differences between dry-milled and wet-milled material may be observed. This may 5280

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