Direct Precipitation of Micron-Size Salbutamol Sulfate - American

Jun 28, 2010 - 10. 3363–3371. Direct Precipitation of Micron-Size Salbutamol Sulfate: New Insights into the Action of Surfactants and Polymeric Addi...
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DOI: 10.1021/cg901270x

Direct Precipitation of Micron-Size Salbutamol Sulfate: New Insights into the Action of Surfactants and Polymeric Additives

2010, Vol. 10 3363–3371

Shuyi Xie,†,‡ Sendhil K. Poornachary,† Pui Shan Chow,† and Reginald B. H. Tan*,†,‡ † Institute of Chemical & Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore 627833, and ‡Department of Chemical and Biomolecular Engineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 117576

Received October 13, 2009; Revised Manuscript Received June 4, 2010

ABSTRACT: Direct precipitation of salbutamol sulfate (SS) by antisolvent crystallization in the presence of surfactants and polymeric additives was investigated to obtain micrometer-sized SS for use in inhaled drug delivery. Among the additives studied — hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP K25), lecithin (from soybean), and Span 85 — PVP K25 showed the strongest effect on crystal growth inhibition. By adding 2.5 mg/mL PVP K25 into the SS solution, the habit of SS crystallized was modified from a needle-like shape to a block-like shape with a lower aspect ratio, and the crystal size was reduced to less than 10 μm. On the basis of the predicted morphology of SS and the possible intermolecular interaction of the additives with a developing SS crystal in solution, we propose that PVP has a higher propensity to form hydrogen bonds with the functional groups that are exposed at the crystal surface. Further supporting evidence based on the effects of PVP concentration and molecular weight on SS crystallization, together with the trends of dispersive surface energy of crystallized SS particles as determined by inverse gas chromatography, strongly suggest that PVP adsorbs on the SS crystals and thereafter inhibits growth.

*Corresponding author. Tel: (65) 6516 6360. Fax: (65) 6779 1936. E-mail: [email protected].

Polymers or surfactants can be used as additives to control crystal growth and suppress aggregation.15-17 It is thought that polymers and surfactants inhibit crystal growth and aggregation by adsorbing on the crystal surfaces. An early study on sulfathiazole crystal growth in the presence of PVP suggested that the polymer forms a net-like structure on the surface, and subsequent growth occurs between the netted pores resulting in formation of finger-like protrusions and a rough surface.18 The higher curvatures of these protrusions eventually increase the minimum supersaturation required for crystal growth. Furthermore, diffusional processes — relative rates of diffusion of the polymer as compared to the solute from the bulk to the crystal surface — controlled the effective concentration of PVP required for growth inhibition. In another related work,19 it was proposed that the strong interactions between the polymer and certain drugs (sulfamethizole and sulfisoxazole) led to inhibition of crystallization of the drug, and consequently, the drug losing its crystal structure in PVP matrix. On the other hand, crystallization of other drugs (sulfamerazine, caffeine, and nalidixic acid) which interacted poorly with PVP was not inhibited, and hence well-defined coprecipitates were not formed with PVP. More recently, the influence of polymers on the antisolvent crystallization of hydrocortisone acetate was studied.20 The mechanism of nucleation retardation by the polymers was explained in terms of association of the solute molecules with the polymer in solution through hydrogen bonding. Growth inhibition was explained based on the presence of a hydrodynamic boundary layer surrounding the crystal and anisotropic adsorption of the polymer on the growing crystal faces. This in turn is dependent on the hydrogen bonding functional groups that are exposed at each facet of the crystal. Investigation of the influence of PVP on crystallization of paracetamol21 found that higher molecular weights of PVP (K10 and K50) were more effective additives than lower molecular weight PVP (K2). With increasing molecular weight and/or concentration of PVP in the solution, the

r 2010 American Chemical Society

Published on Web 06/28/2010

Introduction Inhalation of drug powders is one of the most important administration methods for the treatment of pulmonary diseases. However, achievement of high drug delivery efficiency has been limited by the ability to produce drug particles of the required attributes in terms of size, morphology, and habit.1 Conventionally, micrometer-size particles are produced through milling of larger crystals previously formed in crude crystallization processes.2 High energy input in such methods, however, may result in undesired changes to the drug particles, for instance, changes in crystal polymorphism3 and/or generation of amorphous regions on the drug surface.4 The amorphous materials may then recrystallize in an uncontrolled manner, form solid bridges between particles at high humidity, and consequently, the powder dispersibility may deteriorate during storage.5 In addition, the decrease in crystallinity could facilitate chemical degradation, leading to a decrease in shelf life of the final product. Milled particles have also been reported to exhibit changes in particle size during storage.6,7 Therefore, developing alternative techniques that produce the drug with the desired particle size, morphology, and crystallinity without intensive milling is of significant interest.8 To this end, techniques such as spray drying,9 spray freezedrying,10 supercritical fluid particle formation,11 and antisolvent crystallization12,13 have been suggested for producing fine particles of drug compounds. Among them, antisolvent crystallization has unique advantages because it can be carried out at ambient temperatures and in conventional crystallization vessels. Antisolvent addition generates high supersaturation which favors rapid and abundant nucleation, and hence produces a large number of smaller crystals as compared with cooling and evaporation. However, the rapidly formed crystals tend to aggregate intensively, leading to large particle sizes and broad particle size distributions.14

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induction time for crystallization of paracetamol increased, the amount of PVP adsorbed onto the crystallized particles increased, the percentage recovery of paracetamol decreased, and, at the same time, very thin and flaky crystals were produced. Furthermore, differential scanning calorimetric analysis showed that the onsets of melting point and enthalpies of fusion of paracetamol crystallized in the presence of PVP decreased as compared to the untreated samples. These reductions were attributed to interaction between paracetamol and PVP in the crystals, possibly via hydrogen bonding. In this work, we report antisolvent crystallization of salbutamol sulfate (SS) using polymers and surfactants (lecithin, Span 85, PVP, and HMPC) as additives. SS is a bronchodilator used for the treatment of asthma, chronic bronchitis, and other breathing disorders. In order to achieve high drug delivery efficiency, SS particles should have a tight size distribution (particle size between 1 and 5 μm, with nearly no particles larger than 10 μm).22 We examined the crystal size and habit both in the absence and presence of the additives, and further studied the inhibition mechanism for the selected polymers and surfactants based on molecular interaction of SS and additives using this information. Experimental Section Materials. Salbutamol sulfate (99.0þ% purity) was purchased from Junda Pharm. Chem. Co Ltd. (China). Hydroxypropyl methyl cellulose (HPMC, K10), polyvinylpyrrolidone (PVP K10, K25, K40, and K360), lecithin (asolectin from soybean), and Span 85 were supplied by Sigma-Aldrich. 1-Mythl-N-pyrrolidone was obtained from Merck. Molecular structures of the above additives are shown in Figure 1. Analytical grade ethanol and ultrapure water (Milli-Q Gradient A10, Millipore, USA) were used as antisolvent and solvent, respectively. Crystallization Experiments. Antisolvent crystallization experiments were conducted in a 100 mL beaker (diameter = 5.5 cm) at room temperature (∼23 °C). The SS solution was prepared by dissolving 2 g of SS in 10 mL of water. Appropriate amounts of surfactant or polymer were dissolved in either the drug solution or in ethanol (antisolvent) depending on its solubility in either of the solvents. 90 mL of ethanol was added rapidly into the drug solution with continuous stirring using a magnetic stirrer (length = 2 cm) at 500 rpm. SS crystals were obtained after an induction time varying from 0 to 15 min depending on the type of additive used. The slurry was filtered using filter paper. The crystals were washed with 20 mL of ethanol, dried overnight in a vacuum oven (55 °C and 100 mbar), and stored in a desiccator for further characterization. SS single crystals with distinguishable faces were obtained via slow evaporation of aqueous SS saturated solution at room temperature. PVP was dissolved into water at different concentrations (0-5.0 mg/mL) prior to the addition of SS. The resulting solutions were allowed to evaporate from glass crystallization dishes sealed with a parafilm containing small holes. Microscopy. Scanning electron microscopy (SEM) images of SS crystals were acquired by a JSM-6700 scanning electron microscope (JEOL, Japan). SS samples were coated with platinum using an ion sputter coater (Cressington 208HR, Ted Pella Inc., USA) prior to imaging. The SS crystals obtained from evaporative crystallization experiments were examined using an Olympus BX51 polarized light microscope connected to a CCD camera. Images were recorded using Soft Imaging System’s Analysis image capture software. Particle Size Distribution (PSD). Particle size analysis was performed using a Malvern Mastersizer 2000 equipped with a hydro μP small volume dispersion unit. Ethanol was used as dispersant in all measurements. Samples were subjected to 2500 rpm stirring and 30% ultrasonication for about 2 min to ensure sufficient dispersion. For each crystallization batch, PSD is reported as the average of at least three different sample measurements. Crystal Surface Properties. Dispersive surface energy of SS was analyzed using a SMS-iGC 2000 inverse gas chromatography instrument (Surface Measurement Systems, London, UK). SS sample was

Figure 1. Molecular structures of SS and additives. packed into a presilanized glass column (300  4 mm ID) with silanized glass wool packing at each end to prevent powder movement. The SS samples were pretreated with helium for 16 h at 303 K to remove surface moisture. Adsorption isotherms were measured with a series of purely dispersive n-alkane vapor probes (undecane, decane, nonane, and octane) injected at infinite dilution at 303.15 K. The dispersive surface energy of SS was calculated from net retention volumes using the SMSiGC Standard Analysis Suite based on a peak maximum analysis. Viscosity. A series of PVP solutions in ethanol-water mixture (90%, v/v) at a concentration of 1.0 mg/mL was prepared in the molecular weight range 10-360 K. Viscosity of PVP solutions were studied using an Anton Paar Physica Modular Compact rheometer (MCR-501) at 25 °C using the cylindrical double-gap configuration (DG-26.7). The measuring mode is shear rate controlled, and steps in the shear rate are run for the duration of 15 s. The shear rate ranged from 0 to 5000 s-1. X-ray Diffraction. Powder X-ray diffraction (PXRD) patterns of SS samples were collected using a Bruker D8-Advance X-ray diffractomer (Cu KR radiation of λ = 1.54 A˚ operated at 40 kV and 40 mA voltage and current, respectively) by scanning in the 2θ range of 10° to 40°, at a rate of 0.02°/s. A single crystal (approximate dimensions of 0.11  0.22  0.44 mm) obtained by slow evaporative crystallization of SS in water without additives was placed on a fiber needle and then mounted on the goniometer of the X-ray diffractometer (Rigaku). X-ray reflections were collected on a Rigaku Saturn CCD area detector with graphite monochromated Mo KR radiation (λ = 0.71073 A˚). The diffraction data were processed using CrystalClear (Rigaku) software. The crystal structure was solved by direct methods and expanded using Fourier techniques (SHELXS 97). All non-hydrogen atoms were refined with anisotropic displacement parameters. The hydrogen atoms were fixed at idealized positions and allowed to ride on their parent atoms in the refinement cycles.

Results and Discussion Screening of Polymers and Surfactants. Lecithin, Span 85, PVP K25, and HPMC were screened as additives during

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Figure 2. SS crystals obtained at 30 min after nucleation in the presence of (a) no additives, (b) lecithin, (c) Span 85, (d) HPMC, and (e) PVP K25.

antisolvent crystallization of SS in an attempt to inhibit crystal growth and alleviate aggregation. Lecithin and HPMC (2.0 mg/mL each) and PVP K25 (2.5 mg/mL) were dissolved in the SS aqueous solutions, while Span 85 (2.5 mg/mL) was dissolved in ethanol because of its poor solubility in water. The concentration of additive was calculated based on the amount of additive dissolved in the total volume of the solvent (water þ ethanol) in the final mixed solution. Figure 2a shows the morphologies of SS crystals obtained in the absence of the additives. SS crystals obtained are needle-like and formed aggregates. SS crystals obtained in the presence of lecithin, Span 85, and HPMC also grew as elongated needles (Figure 2c,d). In contrast, SS crystals obtained in the presence of PVP K25 (Figure 2e) are shorter in length, with aspect ratios of about 3-5. This is significantly smaller than the aspect ratio obtained in the presence of other additives (ca. 8-10). Powder X-ray diffraction patterns confirmed that the SS fine particles obtained in the presence of polymers and surfactants are crystalline and are of the same crystal structure as that of SS from pure solution. Table 1 shows the particle size distributions of SS crystals obtained in the presence of polymers and surfactants at 30 min after nucleation has occurred. The difference in the

Table 1. Particle Size Distributions of SS Obtained in the Presence of Additives at 30 min after Nucleation particle size distribution (μm) additives

d(0.1)

d(0.5)

d(0.9)

no additives lecithin Span 85 PVP K25 HPMC

2.05 ((0.05) 0.98 ((0.04) 1.94 ((0.32) 0.32 ((0.26) 0.84 ((0.19)

13.71 ((8.64) 2.91 ((0.15) 29.1 ((6.48) 0.63 ((0.01) 2.20 ((1.89)

80.36 ((29.78) 10.68 ((0.63) 65.78 ((4.29) 6.00 ((0.02) 30.26 ((7.39)

performance of different additives is obvious. The d(0.5) value in the presence of Span 85 is approximately 30 μm which is even higher than that obtained in the absence of additives, demonstrating that Span 85 cannot stabilize the newly formed crystals and prevent crystal growth. In the presence of HPMC, the d(0.5) value is about 2.2 μm, which is much lower than that obtained in the absence of additive, but the d(0.9) value is 34.4 μm which is still very high. This shows that although addition of HPMC controls the size of SS crystals to some extent, the particle size still does not meet the needs for inhalation drugs. In the presence of lecithin, d(0.1), d(0.5), and d(0.9) values are 0.98, 2.91, and 10.68 μm, respectively, and are much lower than those obtained in the absence of additives. The particle size of SS crystals

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Table 2. Comparison of Crystallographic Data of SS Determined in This Work and Reported in CSD crystal system space group lattice parameters

Z V (A˚3) R-factor (%)

CSD (Refcode SALBUT)32

this work

monoclinic Cc a = 28.069 A˚ b = 6.183 A˚ c = 16.914 A˚ R = 90.00° β = 81.19° γ = 90.00° 8 2900.8 6.70

monoclinic C2/c a = 27.890 A˚ b = 6.1857 A˚ c = 16.760 A˚ R = 90.00° β = 98.79° γ = 90.00° 4 2857.5 9.14

obtained in the presence of PVP K25 is the smallest with the value of d(0.1), d(0.5), and d(0.9) at 0.32, 0.63, and 6.00 μm, respectively. From the observations, it could be concluded that PVP K25 is the most effective additive among the four additives tested for inhibition of crystal growth and aggregation, and PVP was selected for further detailed investigation. Crystal Structure and Growth Morphology of SS. The growth morphology of SS was predicted from its crystal structure via molecular modeling-based simulation techniques such as the Bravais-Friedel-Donnay-Harker (BFDH) method23 and the attachment energy (AE) model24 as implemented in Accelrys Materials Studio.25 In the AE model, nonbonded intermolecular interactions within the crystal lattice were calculated using an atom-atom summation method.24 To this end, two different force fields were used: (1) the DREIDING forcefield26 and atomic point charges were assigned for an SS molecule using the charge equilibration (QEq) method;27 (2) the COMPASS force field with force field-assigned atomic point charges.28 A detailed description of the selection of force field potential for simulation of crystal morphology is reported elsewhere.29 The Dreiding-QEq potential set when applied to the crystal structure of SS (Cambridge Structural Database Refcode SALBUT) produced a net negative charge, possibly because the hydrogen atoms were not located for two of the oxygen atoms in the asymmetric unit, and one of the molecules contained an additional oxygen atom. As a result, growth morphology of SS could not be predicted using this potential. To circumvent this problem, the crystal structure of SS was determined experimentally (a comparison of crystallographic data between the reported and current work is shown in Table 2). The slightly higher value of R factor for our crystal structure is reasoned due to twinning of the single crystal used for structure solution. The growth morphology of SS crystal was predicted from the crystal structure determined in this work by the BFDH and the AE methods, respectively. The AE model simulated using the Dreiding potential (Figure 3b), and, to a lesser degree, the BFDH model (Figure 3a) both predicted a higher b/c aspect ratio for SS crystal, indicating that the b axis is intrinsically the fast-growing direction. In order to verify the above prediction, SS crystal growth morphology was also predicted from the reported crystal structure (CSD refcode SALBUT) using the COMPASS force field. In this case, the simulated habit was needle-like and elongated along the b axis (Figure 3c) and is in good agreement with the experimental morphology. The {200}, {002}, and {110} faces were the dominant faces exhibited in the simulated SS crystal morphology. Mechanism of Influence of Polymeric Additives on SS Crystal Growth. In order to understand the mechanism by

Figure 3. Predicted morphology of SS by (a) the BDFH method and (b, c) the AE method using various force field potentials. (b) The Dreiding-QEq potential and (c) the COMPASS force field applied on the crystal structure, respectively.

which the surfactants and polymeric additives inhibited SS crystal growth, we investigated the potential intermolecular interactions between an additive and SS molecules on the dominant crystal faces. To this end, the additive molecule (recurring units of the polymer (PVP and HPMC) and a lecithin molecule) was allowed to approach the SS molecules on the crystal surface. At any particular site on the crystal surface, several orientations of the additive with respect to the surface were tried with the aim to find the orientation that would result in the optimum interaction between the additive and SS crystal surface. However, we note that this approach was based purely on visual representation, and a more rigorous modeling would involve calculation of binding energies for the adsorption of additives onto the crystal surface. The {110} and {111} faces primarily expose the hydroxyl functional groups bonded to the phenyl ring of SS molecule and oriented normal to the facet. A PVP monomer molecule approaching the {110} face (or {111} face) could interact with a SS molecule on the surface through its pyrrolidone fragment forming hydrogen bonds of three different possibilities (Figure 4a), namely, OHsalbut 3 3 3 Opyrrole hydrogen bond (site 1), OHsalbut 3 3 3 Npyrrole hydrogen bond (site 2), and NHsalbut 3 3 3 Opyrrole hydrogen bond (site 3). Of the three hydrogen bonding interactions, the carbonyl group of PVP

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Figure 5. Molecular modeling of interaction between lecithin and SS crystal.

Figure 4. Molecular modeling of (a) interaction of PVP monomer unit with the {110} face of SS crystals, (b, c) molecular topology of the {200} and {002} faces of SS crystals, respectively.

is considered the most favorable site for interactions due to steric constraints on the nitrogen.16 Hence, intermolecular interactions due to OHsalbut 3 3 3 Opyrrole hydrogen bond could contribute to strong binding affinity for PVP on the {110} faces. In contrast, on the {200} and {002} surfaces (Figure 4b,c), the methyl groups of SS are primarily exposed normal to the facet, and therefore, lack potential sites to form hydrogen bonds with the pyrrolidone fragment of PVP. At the same time, on the {200} faces, the HSO4- ions of SS molecule could undergo strong interactions with the solvent (ethanol and water), and consequently, solvation could limit its interactions with PVP. On the {002} faces, the sites exposing hydroxyl groups of salbutamol molecule are submerged in between the ridge-sites exposing the methyl groups, and hence, the surface topology may only favor weaker interactions with PVP as compared to the {110} faces. Consequently, PVP will be preferentially adsorbed on the {110} and {111} faces, and affect further attachment of solute molecules leading to growth inhibition along the b direction. Lecithin, like PVP, exhibited considerable growth inhibition in SS crystals as reflected from the PSD. In order to understand this effect, interactions between a lecithin molecule and SS molecules on the crystal surface were probed. As shown in Figure 5, the lecithin molecule can interact with the hydroxyl group of SS via the phosphonic acid (PO3-) group (site 1) or carbonyl (CdO) group (site 2) potentially forming OHsalbut 3 3 3 Olecithin hydrogen bonds. These types of interactions are specific to the {110} face, and therefore, lecithin could have a stronger binding affinity to that face. Upon adsorption of the polar head groups of lecithin onto the SS crystal surface, the saturated fatty acyl groups protrude from the surface and hence provide a barrier to further crystal growth along the b axis.

Applying a similar methodology, intermolecular interactions between a monomer unit of HPMC and the SS crystal was analyzed. Considering its molecular structure, HPMC has high levels of hydroxyl and methoxy functional groups capable of hydrogen bonding with the hydroxyl and amine functional groups of SS. However, on the {110} face the likelihood of hydrogen bonding between the OHsalbut and CH3OHPMC functional groups is less probable due to steric hindrance caused by the bulkier methyl (and propyl) groups of the polymer additive. Hence, it is postulated that HPMC would have weaker interactions with any of SS crystal faces, and therefore, may not affect its growth significantly. Further experimental data were obtained in order to further substantiate the mechanism of SS crystal growth inhibition by PVP. This involved studying the effects of PVP concentration and molecular weight on SS crystallization and is discussed below. Effects of PVP Concentration on SS Crystallization. SS crystals produced at different concentration levels of PVP K25 in the crystallization medium exhibited a needle-shaped morphology. However, the b/c aspect ratio gradually decreased with an increase in PVP concentration, producing chunkier crystals (Figure 6). This effect was even more apparent from the SS single crystals obtained by the slow evaporation technique (Figure 7a-d). As the PVP concentration was increased from 1.0 to 2.5 mg/mL, the SS crystals exhibited a significant reduction in the b/c aspect ratio along with a change in crystal habit from needle-like to block-like shape. On further increasing the PVP concentration to 5.0 mg/mL, however, no significant reduction in the aspect ratio could be observed. A similar effect of PVP concentration on SS crystallization was also observed from the resulting particle size distribution (Figure 8). The size of SS crystals obtained at 30 min and 24 h after nucleation decreased when the concentration of PVP was increased from 0 to 2.5 mg/ mL. However, the particle size of SS crystals did not decrease any further when the concentration of PVP was increased from 2.5 to 5.0 mg/mL. Besides, SS crystals obtained in the presence of 2.5 mg/mL PVP did not show an increase in particle size even after 24 h, indicating that crystals prepared under this condition were stable against growth and/or aggregation. A direct inference from these morphological changes is that growth inhibition occurs primarily along the b-axis in the presence of PVP, thus corroborating the modeling results. Another additional inference could also be drawn. The magnitude of growth inhibition initially increases with PVP concentration and reaches a maximum beyond which growth

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Figure 6. SS crystals obtained at 24 h after nucleation in the presence of (a) 1.0 mg/mL, (b) 2.5 mg/mL, and (c) 5.0 mg/mL of PVP K25.

Figure 7. SS crystals obtained from evaporation crystallization. The concentrations of PVP K25 added in the experiments are (a) 0 mg/mL, (b) 1.0 mg/mL, (c) 2.5 mg/mL, and (d) 5.0 mg/mL. The scale bar is 1000 μm.

inhibition is less significant. This implies that an equilibrium process, controlled by the adsorption of PVP, could be in action.

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Figure 8. Particle size distribution of SS crystals obtained in the presence of PVP K25 at (a) 30 min and (b) 24 h after nucleation. (c) Comparison of particle size distribution obtained in the presence of 2.5 mg/mL of PVP K25 at different times after nucleation.

Herein, it is emphasized that the levels of supersaturation generated in the antisolvent crystallization is significantly higher than the evaporation method, which influenced the induction time and number of crystals nucleated. Nonetheless, the effect of PVP concentration on SS crystal growth and morphology was consistent between these two methods. Effects of Molecular Weight of PVP on SS Crystallization. In order to validate the interaction mechanism between PVP and SS crystal, 1-methyl-N-pyrrolidone was chosen as a model for the recurring unit of PVP. SS crystals obtained from solutions containing 25.0 mg/mL of methylpyrrolidone (10 times higher concentration than that of polymer additive) displayed an elongated needle-like habit and a d(0.5) of 7.25 μm (Figure 9b and Table 3). In comparison with SS crystals obtained in the absence of any additive (d(0.5) = 13.71 μm), this observation indicates that crystal growth was inhibited in the presence of the monomer. The viscosity of the ethanolwater solution containing monomer at the same concentration (25 mg/mL) were 1.60 and 2.74 cP at shear rates of 128 and 5000 s-1, respectively. This shows only a slight

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Figure 9. SS crystals obtained in the presence of (a) no additives; (b) 25 mg/mL of 1-methyl-N-pyrrolidone; and 1.0 mg/mL of (c) PVP K10; (d) PVP K25; (e) PVP K40; and (f) PVP K360. Table 3. Particle Size Distributions of SS Obtained in the Presence of 1-Methyl-N-pyrrolidone and PVP of Different Molecular Weights particle size distribution (μm) additives no additives 1-methyl-N-pyrrolidone PVP K10 PVP K25 PVP K40 PVP K360

d(0.1)

d(0.5)

d(0.9)

2.05 ((0.05) 13.71 ((8.64) 80.36 ((29.78) 1.51 ((0.12) 7.25 ((0.23) 72.48 ((13.83) 1.15 ((0.07) 5.21 ((0.56) 35.04 ((5.30) 1.02 ((0.04) 4.19 ((0.17) 21.32 ((1.70) 0.78 ((0.09) 2.75 ((0.24) 12.75 ((1.89) 2.45 ((0.19) 13.56 ((4.32) 81.52 ((5.99)

increase as compared to the viscosity of the ethanol-water mixture (1.50 and 2.66 cP at shear rates of 128 and 5000 s-1, respectively), suggesting that mass transfer of the solute molecules to the crystal surface is not the rate-limiting step for growth inhibition of SS crystals. On the other hand, specific interactions between the monomer and SS molecules at the crystal surface, possibly via hydrogen bonding, could lead to a retarding effect on crystal growth. However, the extent of growth inhibition by the monomer is not strong enough to produce a significant habit change as observed with PVP K25. We reason that this could be because the repeating units of PVP can provide greater H-bonding

propensity with the SS crystal surface in comparison with the monomer unit. Moreover, as proposed by Simonelli et al.,18 a net-like structure at the crystal-solution interface could be formed with PVP and thereby result in an extra barrier for crystal growth. The growth inhibition mechanism was further investigated to include the effect of molecular weight of PVP. Figure 9c-f shows the resulting crystals from different experiments using 1.0 mg/mL of PVP of molecular weights K10, K25, K40, and K360, respectively, and their respective PSDs are shown in Table 3. At 1.0 mg/mL concentration, PVP K10 produced smaller crystals with a size along the b direction measured around 5 μm. At the same concentration of PVP K25, SS crystals obtained were measured to be less than 5 μm along the b axis. Addition of PVP K40 further reduced the crystal size to approximately 1 μm long, which is not suitable for inhalation applications. Interestingly, the highest molecular weight (PVP K360) did not follow the trend, but produced crystals of approximately 10 μm long. These results show a direct relationship between PVP molecular weight and the extent of crystal growth inhibition. Thus, for the range of molecular weights K10-K40, a higher molecular weight of PVP can provide higher concentration of the recurring vinyl

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pyrrolidone segments interacting with the crystal surface, and therefore, a greater adsorbing tendency and, subsequently resulting in stronger growth inhibition effect. On the other hand, for PVP K360, the rate of PVP diffusion to the surface may be the rate determining step for the polymercrystal interaction. This argument was indeed supported by the measured viscosity of the crystallizing medium in the presence PVP of different molecular weights. For PVP K10 to K40, the solution viscosity ranges from 1.51 to 1.54 cP at a minimum shear rate of 128 s-1, and from 2.69 to 2.72 cP at a maximum shear rate of 5000 s-1, showing only a 1-2% increase when the molecular weight increases from K10 to K40; however, for PVP K360, the solution viscosity is 1.84 cP at 128 s-1, which is 19% higher compared to that of PVP K40, and 3.03 cP at 5000 s-1, corresponding to 11% increase compared to that of PVP K40. From the above Results and Discussion, we draw the following conclusions: with PVP of a lower molecular weight (K10 and K40), inhibition of SS crystal growth is controlled by the adsorption of the polymer on the crystal surface, whereas for the higher molecular weight PVP (K360), the crystal growth inhibition mechanism is diffusion controlled. This latter observation is consistent with Simonelli et al.,18 wherein the authors noted that the inhibition of crystal growth (sulfathiazole) was only controlled by the relative rates of diffusion of the polymer (PVP) to the crystal surface. Variation of Crystal Surface Energy. The crystallization experimental results and the molecular analysis suggest that when PVP is adsorbed on the SS crystal surface, the nonpolar functional groups of PVP should be exposed. This would in turn be reflected by a change in the dispersive surface energy. On the basis of this assumption, inverse gas chromatography (IGC) analysis was performed with nonpolar probes to determine surface energy of SS crystallized from solutions added with PVP K25 at different concentrations. The net retention volume (VN) in IGC is a fundamental surface thermodynamic property, which can be obtained and related to the surface properties. The net retention volume of each alkane injection is related to the dispersive surface energy component (γds ) via RT ln VN ¼ aðγds Þ1=2 2Nðγdl Þ1=2 þ C

ð1Þ

where a is the molecular area of adsorbate; N is the Avogadro’s number; γds and γdl are dispersive components of surface free energy of the solid and liquid probe, respectively. C is a constant.30 By plotting RT ln VN vs a(Vdl )1/2 for five nalkane nonpolar adsorbates, the slope of the straight line gives the dispersive component of surface energy (γds ). Table 4 shows that the values of dispersive surface energy of SS crystals decreased with the increase in PVP K25 concentration in solution. Although IGC does not provide face-specific information, the measured values of dispersive surface energy reflect the total amount of nonpolar functional groups exposed on the SS crystal surfaces. Taking into consideration SS crystal habit changes in the presence of the polymer additive, simultaneous reduction in the values of dispersive surface energy could be reasoned in two different ways. First, it could be due to the deposition of PVP on the surface of SS crystals along the b direction through favorable interactions between the vinyl pyrrolidone groups of PVP and the polar faces of SS crystals. Note that PVP K25 has a lower dispersive surface energy as compared to SS (Table 4).

Table 4. Dispersive Surface Energy Values (γds ) of SS and PVP K25 Particles samples

γds (mJ/m2)

SS (unprocessed) SS/PVP K25 (1.0 mg/mL) SS/PVP K25 (2.5 mg/mL) SS/PVP K25 (5.0 mg/mL) PVP K25

117.5 ((5.8) 104.9 ((3.0) 86.0 ((8.4) 73.1 ((6.6) 54.3 ((5.3)

Consequently, with the increase in PVP concentration adsorbed on the surface of SS crystals, the dispersive surface energy would decrease. Second, the shortening of SS crystals along the b direction with the addition of PVP leads to a higher proportion of polar faces (i.e., {110} and {111}) being exposed in the crystal habit, thus resulting in a decrease in dispersive surface energy. By both means, reduction of dispersive surface energies supports our proposed mechanism that underpins the effect of PVP on the crystallization of SS. Conclusions In this work, we have employed antisolvent crystallization in the presence of a polymeric additive (PVP) to directly produce SS particles of size distribution suitable for inhalation drug delivery. By studying the molecular interactions between the additives and SS crystal surface, we have proposed that PVP adsorbs selectively on the crystal surface based on the H-bonding ability of the polymer with the crystal surface and inhibits growth along the b-axis. Experimental data on the effect of PVP concentration and molecular weight have also been obtained and found to be supportive of the proposed mechanism. Surface dispersive energy measurement by IGC suggests that PVP is adsorbed on the crystal surface, which agrees with the proposed mechanism. It can be seen that our molecular modeling analysis gives a good qualitative picture of the intermolecular interactions between the polymer and the crystal surface, and in this direction, empirical molecular modeling can provide a useful tool. A more rigorous approach involving molecular dynamics calculations by considering the adsorption profile of the monomer unit (or a larger fragment of polymer chain) with the crystal face as a function of simulation time31 would be a logical extension to this work. Acknowledgment. We thank Dr. Srinivasulu Aitipamula for solving the single crystal XRD structure of salbutamol sulphate.

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